Gastin and CCK receptor ligands

ABSTRACT

Compounds of formula (Ia), (Ib), or (Ic), wherein A represents a group having two fused rings, or a group of formula (Id), R 1 .sub.(m) represents up to 6 substituents, K represents --O--, --S--, --CH 2  --, --N(R 2 )-- or --N(COR 2 )--, in which R 2  is H or C 1  to C 3  alkyl, W is a carbonyl, sulfonyl or sulfinyl group, provided that at least one of W and X contains carbonyl, Y and Z are as given in the description, and their pharmaceutically acceptable salts are ligands at CCK and/or gastrin receptors. ##STR1##

This application is a National Stage filing of PCT/GB94/01741, filedAug. 9, 1994.

This invention relates to gastrin and CCK receptor ligands. Theinvention also relates to methods for preparing such ligands and tocompounds which are useful as intermediates in such methods.

Gastrin and the CCK's are structurally-related neuropeptides which existin gastrointestinal tissue and in the CNS (see Mutt V., GastrointestinalHormones, Glass G. B. J., ed., Raven Press, N.Y., p 169 and Nisson G.,ibid, p. 127).

Gastrin is one of the three primary stimulants of gastric acidsecretion. Several forms of gastrin are found including 34-, 17-, and14-amino acid species with the minimum active fragment being theC-terminal tetrapeptide (TrpMetAspPhe-NH₂) which is reported in theliterature to have full pharmacological activity (see Tracey H. J. andGregory R. A., Nature (London), 1964, 204, 935). Much effort has beendevoted to the synthesis of analogues of this tetrapeptide (and theN-protected derivative Boc-TrpMetAspPhe-NH₂) in an attempt to elucidatethe relationship between structure and activity.

Natural cholecystokinin is a 33 amino acid peptide (CCK-33), theC-terminal 5 amino acids of which are identical to those of gastrin.Also found naturally is the C-terminal octapeptide (CCK-8) of CCK-33.

The cholecystokinins are reported to be important in the regulation ofappetite. They stimulate intestinal motility, gall bladder contraction,pancreatic enzyme secretion, and are known to have a trophic action onthe pancreas. They also inhibit gastric emptying and have variouseffects in the CNS.

Compounds which bind to cholecystokinin and/or gastrin receptors areimportant because of their potential pharmaceutical use as antagonistsof the natural peptides.

A number of gastrin antagonists have been proposed for varioustherapeutic applications, including the prevention of gastrin-relateddisorders, gastrointestinal ulcers, Zollinger-Ellison syndrome, antral Gcell hyperplasia and other conditions in which lowered gastrin activityis desirable. The hormone has also been shown to have a trophic actionon cells and so an antagonist may be expected to be useful in thetreatment of cancers, particularly in the stomach and the colon.

Possible therapeutic uses for cholecystokinin antagonists include thecontrol of appetite disorders such as anorexia nervosa, and thetreatment of pancreatic inflammation, biliary tract disease and variouspsychiatric disorders. Other possible uses are in the potentiation ofopiate (e.g. morphine) analgesia, and in the treatment of cancers,especially of the pancreas. Moreover, ligands for cholecystokininreceptors in the brain (so-called CCK_(B) receptors) have been claimedto possess anxiolytic activity.

According to the present invention, there are provided compounds of theformula ##STR2## wherein A represents a bicyclic group (meaning a grouphaving two fused rings, in which the atoms which are common to the tworings are joined by a single or multiple bond), W and X replacinghydrogen on adjacent atoms (most usually adjacent carbon atoms), or A isa group of the formula ##STR3## in which W and X replace hydrogen onadjacent carbon atoms, m is from 0 to 6, provided that m is not morethan 2 unless R¹ is exclusively halo,

R¹ is halo, amino, amidino, nitro, cyano, hydroxy, sulphamoyl,hydroxysulphonyl, carboxy, esterified carboxy, amidated carboxy,tetrazolyl, C₁ to C₈ alkyl (particularly C₁ to C₆ alkyl), aryl,substituted aryl, C₁ to C₆ hydroxyalkyl, C₁ to C₆ haloalkyl, C₁ to C₆alkoxy, C₁ to C₆ alkylcarboxyamino, HON═C--, R²⁷ --SO₂ --NH--, R²⁷ --SO₂--NH--CO--, R²⁷ --CO--, R²⁷ --CO--NH--, R²⁷ --CO--NH--SO₂ --, R²⁷--CO--NH--SO-- or R²⁸ --NH--SO₂ --, wherein R²⁷ is H (except when R²⁷ isattached to a sulphur atom), C₁ to C₆ alkyl, C₁ to C₆ haloalkyl, aryl orsubstituted aryl, and R²⁸ is H, C₁ to C₆ alkyl, C₁ to C₆ haloalkyl,aryl, substituted aryl, --OH or --CN (each R¹ group, when m is 2 ormore, being independently selected from the foregoing),

K represents --O--, --S--, --CH₂ --, --N(R²)-- or --N(COR²)--, in whichR² is H or C₁ to C₃ alkyl,

W is a carbonyl, sulphonyl or sulphinyl group, and X is a carbonyl,sulphonyl or sulphinyl group, provided that at least one of W and Xcontains carbonyl,

Y is R³ --N(R⁴)-- or R^(3') --O-- (wherein R³ is H or C₁ to C₁₅hydrocarbyl, one or more hydrogen atoms of the hydrocarbyl moietyoptionally being replaced by halogen atoms, and up to two carbon atomsof the hydrocarbyl moiety optionally being replaced by a nitrogen,oxygen or sulphur atom, R^(3') is C₆ to C₁ s hydrocarbyl, one or morehydrogen atoms of the hydrocarbyl moiety optionally being replaced byhalogen atoms, and up to two carbon atoms of the hydrocarbyl moietyoptionally being replaced by a nitrogen, oxygen or sulphur atom, and R⁴is H, C₁ to C₃ alkyl, carboxymethyl or esterified carboxymethyl),provided that Y does not contain a --O--O-- group, and

Z is selected from

i) --O--R⁵

wherein R⁵ is H, C₁ to C₅ alkyl, phenyl, substituted phenyl, benzyl orsubstituted benzyl;

ii) ##STR4## wherein Q is H, C₁ to C₅ hydrocarbyl, or --R⁶ --U, whereinR⁶ is a bond or C₁ to C₅ (eg. C₁ to C₃) alkylene and U is aryl,substituted aryl, heterocyclic, substituted heterocyclic or cycloalkyl(preferably cyclohexyl or cycloheptyl),

iii) ##STR5## wherein a is 0 or 1 and b is from 0 to 3, R⁷ is H ormethyl,

R⁸ is H or methyl; or R⁸ is CH₂ ═ and Q' is absent; or R⁷ and R⁸ arelinked to form a 3- to 7-membered ring,

R⁹ is a bond or C₁ to C₅ hydrocarbylene,

G is a bond, --CHOH-- or --C(O)--

Q' is as recited above for Q or --R⁶ --(C(O)_(d) --L--(C(O))_(e) --R⁵(wherein R⁵ and R⁶ are as defined above, L is O, S or --N(R¹⁰)--, inwhich R¹⁰ is as defined above for R⁴, and d and e are 0 or 1, providedthat d+e<2); or Q' and R⁸, together with the carbon atom to which theyare attached, form a 3- to 7-membered ring,

Q is as defined above; or Q and R⁸ together form a group of the formula--(CH₂)_(f) --V--(CH₂)_(g) -- wherein V is --S--, --S(O)--, --S(O)₂ --,--CH₂ --, --CHOH-- or --C(O)--, f is from 0 to 2 and g is from 0 to 3;or, when Q' is --R⁶ --U and U is an aromatic group, Q may additionallyrepresent a methylene link to U, which link is ortho to the R⁶ link toU,

T is H, cyano, C₁ to C₄ alkyl, --CH₂ OH, carboxy, esterified carboxy,amidated carboxy or tetrazolyl; or

iv) ##STR6## wherein R⁵ and R⁶ are as defined above, R¹¹ is as definedabove for R⁴, and R¹² and R¹³ are independently a bond or C₁ to C₃alkylene, provided that R¹² and R¹³ together provide from 2 to 4 carbonatoms in the ring,

and pharmaceutically acceptable salts thereof.

Certain compounds of the invention exist in various regioisomeric,enantiomeric, tautomeric and diastereomeric forms. It will be understoodthat the invention comprehends the different regioisomers, enantiomers,tautomers and diastereomers in isolation from each other, as well asmixtures.

The term "hydrocarbyl", as used herein, refers to monovalent groupsconsisting of carbon and hydrogen. Hydrocarbyl groups thus includealkyl, alkenyl, and alkynyl groups (in both straight and branched chainforms), cycloalkyl (including polycycloalkyl), cycloalkenyl, and arylgroups, and combinations of the foregoing, such as alkylaryl,alkenylaryl, alkynylaryl, cycloalkylaryl, and cycloalkenylaryl groups,

A "carbocyclic" group, as the term is used herein, comprises one or moreclosed chains or rings, which consist entirely of carbon atoms. Includedin such groups are alicyclic groups (such as cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and adamantyl), groups containing both alkyl andcycloalkyl moieties (such as adamantanemethyl), and aromatic groups(such as phenyl, naphthyl, indanyl, fluorenyl,(1,2,3,4)-tetrahydronaphthyl, indenyl and isoindenyl) . The term "aryl"is used herein to refer to aromatic carbocyclic groups, including thosementioned above.

A "heterocyclic" group comprises one or more closed chains or ringswhich have at least one atom other than carbon in the closed chain orring. Examples include benzimidazolyl, thienyl, furanyl, pyrrolyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl,pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl,piperidyl, piperazinyl, morpholinyl, thionaphthyl, benzofuranyl,isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl,7-azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl,quinolyl, isoquinolyl, naphthridinyl, cinnolinyl, quinazolinyl,pyridopyridyl, benzoxazinyl, quinoxadinyl, chromenyl, chromanyl,isochromanyl and carbolinyl.

The term "halogen", as used herein, refers to any of fluorine, chlorine,bromine and iodine. Most usually, however, halogen substituents in thecompounds of the invention are chlorine or fluorine substituents.

When reference is made herein to a "substituted" aromatic group, thesubstituents will generally be from 1 to 3 in number (and more usually 1or 2 in number), and generally selected from the groups recited abovefor R¹. However, halo substituents may be up to 5 in number.

Preferably, m is 0. However, when m is not 0, R¹ is preferably selectedfrom halo, amino, nitro, cyano, sulphamoyl, sulphonyl, trifluoromethyl,C₁ to C₃ alkyl, hydroxy, C₁ to C₃ hydroxyalkyl, C₁ to C₃ alkoxy, C₁ toC₃ alkylcarboxyamino, carboxy, esterified carboxy, amidated carboxy andtetrazolyl, and more preferably from halo, amino, nitro, cyano,sulphamoyl, C₁ to C₃ alkyl and C₁ to C₃ alkoxy. As mentioned above, whenm is 2 or more, each R¹ group is independent of the others. For example,the compounds of the invention may include two different R¹ groups.

An "esterified" carboxy group, as the term is used herein, is preferablyof the form --COOR¹⁴, wherein R¹⁴ is C₁ to C₅ alkyl, phenyl, substitutedphenyl, benzyl, substituted benzyl, indanyl, or one of the following:##STR7##

Most commonly, R¹⁴ is C₁ to C₅ alkyl, benzyl or substituted benzyl, andparticularly C₁ to C₅ alkyl.

"Amidated" carboxy groups include alkoxyamido groups (particularly C₁ toC₆ alkoxyamido groups), but are more usually of the form --CONR¹⁵ R¹⁶wherein R¹⁵ is H, C₁ to C₅ alkyl, phenyl, substituted phenyl, benzyl orsubstituted benzyl, and R¹⁶ is --OH or one of the groups just recitedfor R¹⁵.

In the case of the group T, preferred amidated carboxy groups take theform --CONR¹⁵ R¹⁶ (wherein R¹⁵ and R¹⁶ are as defined above) or ##STR8##wherein R¹⁵ is as defined above, R¹⁷ and R¹⁸ are independently H ormethyl, or R¹⁷ and R¹⁸ (together with the carbon atom to which they areattached) form a 3- to 7-membered carbocyclic group, J is --OH, --O--R¹⁴or --NHR¹⁶, wherein R¹⁴ and R¹⁶ are as defined above, and x is 0 to 3.

When R⁷ and R⁸ are linked to form a ring, such ring will generally besaturated, and usually also carbocyclic. Similarly, when Q' and R⁸ arelinked to form a ring, this will also usually be saturated andcarbocyclic.

Exemplary carbocyclic and heterocyclic groups which may form the group Uinclude: ##STR9## wherein R¹⁹ is as defined above for R¹, and h is from0 to 3 (or up to 5 when R¹⁹ is exclusively halo), and ##STR10## whereinP is H or --COOR²⁰, in which R²⁰ is as defined above or R¹⁵.

Z is preferably --NH₂, --O--R⁵ or ##STR11## wherein i is from 0 to 4, jis from 0 to 3, R²¹ and R²² are independently H or methyl, or R²¹ andR²² together form a group of the formula --(CH₂)_(k) --V'--CH₂ --(wherein V' is --CH₂ --, --CHOH-- or --C(O)--, and k is 0 to 2). Mostcommonly, i is 0 or 1 and j is 0 to 2.

When W is sulphinyl, Y is preferably R³ --NH--.

Preferably, R³ is C₆ to C₈ straight or branched chain alkyl, or R²³--(CH₂)_(p) --, wherein R²³ is selected from phenyl, 1-naphthyl,2-naphthyl, indolyl, norbornyl, adamantyl, cyclohexyl or cycloheptyl,and p is from 0 to 3.

Favoured bicyclic groups to form A in formula (Ia) above include##STR12## wherein R²⁴ is H, C₁ to C₈ alkyl or R²⁵ --CO--R²⁵ is H or C₁to C₈ (eg. C₁ to C₃) alkyl

D and D' are independently --CH═, --N═ or --SR²⁶ ═ (R²⁶ being H or C₁ toC₃ alkyl, or R²⁶ is absent and the sulphur atom is positively charged)

E is --CH═ or --N═

M is --CR²⁴ ═, --N═ or --C(NR²⁴ R²⁵)═ (wherein R²⁴ and R²⁵ are asdefined above), and

F is --O--, --S--, --CH₂ -- or --NR²⁴ -- (wherein R²⁴ is as definedabove).

Preferably, the compounds of the invention are of the formula: ##STR13##(wherein W and X are attached to adjacent carbon atoms; R³² is H, C₁ toC₃ alkyl or C₁ to C₃ alkylcarboxy; and L' is --NR³² --, --O-- or --S--),##STR14##

Also preferred are compounds in which

--X--Y is --CONR³ R⁴ (R³ and R⁴ being as defined above), and

--W--Z is ##STR15## (wherein R²⁹, R³⁰ and R³¹ are independently H or C₁to C₃ alkyl; U' is an (optionally substituted) aromatic group; n is 1 or2; Y is --CO₂ H, tetrazolyl, esterified carboxy, amidated carboxy, R²⁷--SO₂ --NH--, R²⁷ --SO₂ --NH--CO--, R²⁷ --CO--, R²⁷ --CO--NH--, R²⁷--CO--NH--SO₂ --, R²⁷ --CO--NH--SO-- or R²⁸ --NH--SO₂ -- (R²⁷ and R²⁸being as defined above), each Y being independently selected from theforegoing when n is 2; and c is from 0 to 2).

Compounds according to the present invention in which W is a carbonylgroup, X is carbonyl or sulphonyl, and Z is OH may conveniently be madeby reacting a compound of the formula YH (ie. either an alcohol or anamine) with a compound of the formula ##STR16## wherein B represents##STR17##

If YH is an amine, the reaction is suitably carried out in a solventsuch as THF in the presence of a base such as DMAP. If YH is an alcohol,the reaction may be conducted in pyridine at elevated temperature.

Compounds in which Z is other than OH may of course be made from theacid compound ##STR18## by conventional esterification or amidationreactions on suitably protected derivatives. Suitable amidation methodsare described in detail in "The Peptides, Vol. 1", Gross andMeinenhofer, Eds., Academic Press, N.Y., 1979. These include thecarbodiimide method (using, for example, 1,3-dicyclohexylcarbodiimideDCC! or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlorideEDCI!, and optionally an additive such as 1-hydroxybenzotriazole HOBT!to prevent racemization), the azide method, the mixed anhydride method,the symmetrical anhydride method, the acid chloride method, the acidbromide method, the use of bis (2-oxo-3-oxazolidinyl) phosphinicchloride BOP-Cl!, the use of PyBOP or PyBrOP, the use of theisopropenylsuccinimido carbonate method and the active ester method(using, for example, N-hydroxysuccinimide esters, 4-nitrophenyl estersor 2,4,5-trichlorophenol esters). The coupling reactions are generallyconducted under an inert atmosphere, such as an atmosphere of nitrogenor argon. Suitable solvents for the reactants include methylenechloride, tetrahydrofuran THF!, dimethoxyethane DME! anddimethylformamide DMF!.

Bisamides according to the present invention may alternatively beprepared by reacting a compound of formula (II) with a suitablyprotected derivative of ZH, followed by conventional amidation asdescribed above.

An analogous procedure may also be used as the basis for preparing thecompounds of the invention in which W is sulphonyl and Y is R³ --O--, asdepicted in reaction scheme A below: ##STR19##

In this case, the mixed anhydride (IV) is opened with an alcohol such asbenzyl alcohol (represented as ROH), so that the product is thecorresponding sulphonyl ester (V). The free carboxylic acid group ofthis sulphonyl ester may then be esterified by conventional methods,followed by hydrogenolysis of the product (VI) to yield the desiredsulphonic acid carboxylic ester (VII).

The compounds of the invention in which W is sulphonyl and Y is R³--NH-- may be prepared by analogous means, in which compound (V) isamidated (rather than esterified) prior to hydrogenolysis.Alternatively, a process such as is depicted in reaction scheme B may beemployed: ##STR20##

In this scheme, compound (VIII) is reacted with a compound of theformula R³ -Hal (wherein Hal represents a halogen atom) to form compound(IX). The N-containing ring may then be opened using an alkoxide (eg.sodium methoxide in methanol) to produce the target compound (X).

The invention therefore also provides a method of making compoundswherein W is sulphonyl and Y is R³ --NH--, said method comprising thestep of reacting a compound of formula (VIII) with a compound of theformula R³ -Hal, and then reacting the product with an alkoxide.

Compounds of the invention wherein W or X is a sulphoxide group mayconveniently be prepared by the route shown in reaction scheme C:##STR21##

Compound (XII) can then be opened both ways to give on the one hand thesulphinamide acid alkyl ester (XIII), and on the other the sulphinicacid amide (XIV). The free sulphinamide acid can of course be obtainedfrom the alkyl ester (XIII) by conventional methods.

Accordingly, the invention also provides a method of making compoundswherein W or X is sulphoxide, said method comprising the step ofreacting a compound of formula (XI) with a compound of the formula R³-Hal, and then reacting the product with an alkoxide.

While reaction schemes B and C above lead to the free sulphonic orsulphinic acid compounds, it will be appreciated that the correspondingester or amide derivatives can be prepared from the free acid compoundsby conventional methods. Most usually, coupling of the sulphonic orsulphinic acid compounds will be via the corresponding sulphonic orsulphinic acid chlorides.

Pharmaceutically acceptable salts of the acidic or basic compounds ofthe invention can of course be made by conventional procedures, such asby reacting the free base or acid with at least a stoichiometric amountof the desired salt-forming acid or base.

The compounds of the invention can be administered by oral or parenteralroutes, including intravenous, intramuscular, intraperitoneal,subcutaneous, rectal and topical administration.

For oral administration, the compounds of the invention will generallybe provided in the form of tablets or capsules or as an aqueous solutionor suspension.

Tablets for oral use may include the active ingredient mixed withpharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavouring agents, colouring agents and preservatives. Suitableinert diluents include sodium and calcium carbonate, sodium and calciumphosphate, and lactose, while corn starch and alginic acid are suitabledisintegrating agents. Binding agents may include starch and gelatin,while the lubricating agent, if present, will generally be magnesiumstearate, stearic acid or talc. If desired, the tablets may be coatedwith a material such as glyceryl monostearate or glyceryl distearate, todelay absorption in the gastrointestinal tract.

Capsules for oral use include hard gelatin capsules in which the activeingredient is mixed with a solid diluent, and soft gelatin capsuleswherein the active ingredient is mixed with water or an oil such aspeanut oil, liquid paraffin or olive oil.

For intramuscular, intraperitoneal, subcutaneous and intravenous use,the compounds of the invention will generally be provided in sterileaqueous solutions or suspensions, buffered to an appropriate pH andisotonicity. Suitable aqueous vehicles include Ringer's solution andisotonic sodium chloride. Aqueous suspensions according to the inventionmay include suspending agents such as cellulose derivatives, sodiumalginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agentsuch as lecithin. Suitable preservatives for aqueous suspensions includeethyl and n-propyl p-hydroxybenzoate.

Effective doses of the compounds of the present invention may beascertained by conventional methods. The specific dosage level requiredfor any particular patient will depend on a number of factors, includingthe severity of the condition being treated and the weight of thepatient. In general, however, the daily dose (whether administered as asingle dose or as divided doses) will be in the range 0.001 to 5000 mgper day, and more usually from 1 to 1000 mg per day. Expressed as dosageper unit body weight, a typical dose will be between 0.01 μg/kg and50mg/kg, eg between 10 μg/kg and 10 mg/kg.

The invention is now further illustrated by means of the followingexamples.

EXAMPLE 1

3-(1-adamantanemethylaminocarbonyl)-2-naphthoic acid

2,3-naphthalenedicarboxylic anhydride (198 mg, 1.0 mmol) and1-adamantanemethylamine (176 mg, 1.0 mmol) were dissolved in dry THF (5ml) and stirred at room temperature for 1 h. A thick white precipitatewas formed and this was isolated by filtration and washed with ether toleave the title compound (229 mg, 69%), ¹ H NMR (d⁶ -DMSO) δ 12.9 (1H,s), 8.3 (2H, s), 8.1 (2H, t), 7.9 (1H, s), 7.6 (2H, m), 2.9 (2H, d), 1.9(3H, s), 1.6 (6H, q), 1.5 (6H, s).

The material was further characterised and tested as theN-methyl-D-glucamine salt found: C, 62.36; H, 7.77; N, 4.60. C₃₀ H₄₂ N₂O₈. H₂ O requires C, 62.48; H, 7.69; N, 4.85%

EXAMPLE 2

2-(1S-methoxycarbonyl-ethylaminocarbonyl)-3-(1-adamantanemethylaminocarbonyl)-naphthalene

3-(1-adamantanemethylaminocarbonyl)-2-naphthoic acid (229 mg, 0.52mmole)(the compound of example 1) and PyBOP (312 mg, 0.6 mmole) weretaken up in dry dichloromethane (5 ml) and Hunigs base (0.32 ml, 1.5mmole) was added. The reaction mixture was stirred under an atmosphereof dry argon for 1 h. L-alanine methyl ester hydrochloride (80 mg, 0.6mmole) was added and the mixture stirred overnight. The organic layerwas washed with 5% potassium hydrogensulphate (5 ml), sodiumhydrogencarbonate (5 ml) and saturated brine (5 ml). It was then dried,filtered and evaporated to leave the crude title compound which wasfurther purified by column chromatography (silica 4% methanol and 96%dichloromethane. The title compound (194 mg, 67%) was isolated as awhite solid, m.p. 136°-8°, found: C, 69.68; H, 7.17; N, 6.04. C₂₇ H₃₂ N₂O₄. H₂ O requires C, 69.51; H, 7.34; N, 6.00% ¹ H NMR (CDCl₃) δ 8.0 (1H,s), 7.9 (1H, s), 7.8 (2H, m), 7.6 (3H, m), 7.0 (1H, t), 4.8 (1H, m), 3.8(3H, s), 3.2 (2H, m), 2.0 (3H, s), 1.8 (6H, q), 1.6 (6H, s), 1.5 (3H,d).

EXAMPLE 3

3-(2R-carboxypyrrolidino-carbonyl)-2-(1-adamantanemethylaminocarbonyl)-naphthalene

a.3-(2R-benzyloxycarbonyl-pyrrolidino-carbonyl)-2-(1-adamantanemethylaminocarbonyl)-naphthalene

The material was made essentially as in example 2 except that D-prolinebenzyl ester hydrochloride was used as substrate instead of L-alaninemethyl ester hydrochloride.

b.3-(2R-carboxy-pyrrolidino-carbonyl)-2-(1-adamantanemethylaminocarbonyl)-naphthalene

The product of step a (195 mg, 0.35 mmol) was dissolved in THF (5 ml)and 10% palladium on charcoal (20 mg) was added. The reaction mixturewas stirred overnight under an atmosphere of hydrogen and then filteredthrough celite and evaporated to yield the title compound (121 mg, 76%),¹ H NMR (d⁶ -DMSO) δ 12.6 (1H, s), 8.4 (1H, t), 8.2-7.5 (6H, m), 4.3(1H, m), 3.6-2.2 (6H, m), 2.0 (2H, m), 1.8 (3H, s), 1.5 (6H, q), 1.4(6H, s).

The material was further characterised and tested as theN-methyl-D-glucamine salt found: C, 60.00; H, 7.60; N, 5.85. C₃₅ H₄₉ N₃O₉.2.4 H₂ O requires C, 60.12; H, 7.76; N, 6.00%

EXAMPLE 4

2-(2S-carboxypyrrolidino-carbonyl)-3-(1-adamantanemethylaminocarbonyl)-naphthalene

The material was prepared essentially as in example 3 except thatL-proline benzyl ester hydrochloride was used in step a instead ofD-proline benzyl ester hydrochloride, ¹ H NMR (d⁶ -DMSO) δ 12.6 (1H, s),8.4 (1H, t), 8.2-7.5 (6H, m), 4.3 (1H, m), 3.6-2.2 (6H, m), 2.0 (2H, m),1.8 (3H, s), 1.5 (6H, q), 1.4 (6H, s).

The material was further characterised and tested as theN-methyl-D-glucamine salt found: C, 61.62; H, 6.98; N, 6.09. C₃₅ H₄₉ N₃O₉.0.45 DCM requires C, 61.35; H, 7.24; N, 6.05%

EXAMPLE 5

2-(1R-carboxyethylamino-carbonyl)-3-(1-adamantanemethylaminocarbonyl)-naphthalene

The material was prepared essentially as in example 3 except thatD-alanine benzyl ester hydrochloride was used in step a instead ofD-proline benzyl ester hydrochloride, ¹ H NMR (d⁶ -DMSO) δ 12.6 (1H, s),8.7 (1H, d), 8.3 (1H, t), 8.1-7.5 (6H, m), 4.4 (1H, m), 2.9 (2H, 2×dd),1.9 (3H, s), 1.6 (6H, q), 1.5 (6H, s), 1.3 (3H, d).

The material was further characterised and tested as theN-methyl-D-glucamine salt found: C, 61.52; H, 7.54; N, 6.92. C₃₃ H₄₇ N₃O₉.0.9 H₂ O requires C, 61.87; H, 7.58; N, 6.56%

EXAMPLE 6

2-(2S-methoxycarbonylpyrrolidino-carbonyl)-3-(1-adamantanemethylaminocarbonyl)-naphthalene

The compound of example 4 (88 mg, 0.18 mmol) was dissolved in diethylether (30 ml) and an ethereal solution of diazomethane was added untilthe solution remained yellow. Acetic acid was added to quench thereaction and the solvent was removed by evaporation the last traces byazeotrope with dichloromethane. The solid was dried in vacuo to leavethe title compound (61 mg, 67 %). found: C, 62.46; H, 6.55; N, 5.19. C₂₉H₃₄ N₂ O₄.1.22 DCM requires C, 62.77; H, 6.35; N, 4.84% ¹ H NMR (d⁶-DMSO) δ 8.4 (1H, t), 8.2-7.5 (6H, m), 4.4 (1H, m), 3.7 (3H, s), 3.6-2.2(6H, m), 2.0 (2H, m), 1.8 (3H, s), 1.5 (6H, q), 1.4 (6H, s).

EXAMPLE 7

2-(2R-methoxycarbonylpyrrolidino-carbonyl)-3-(1-adamantanemethylaminocarbonyl)-naphthalene

The compound was prepared as in example 6 except that the compound ofexample 3 was used as substrate instead of the compound of example 4.found: C, 69.96; H, 7.06; N, 5.68. C₂₉ H₃₄ N₂ O₄.1.16 H₂ O requires C,70.30; H, 7.39; N, 5.65% ¹ H NMR (d⁶ -DMSO) δ 8.4 (1H, t), 8.2-7.5 (6H,m), 4.4 (1H, m), 3.7 (3H, s), 3.6-2.2 (6H, m), 2.0 (2H, m), 1.8 (3H, s),1.5 (6H, q), 1.4 (6H, s).

EXAMPLE 8

2-(1R-methoxycarbonylethylamino-carbonyl)-3-(1-adamantanemethylaminocarbonyl)-naphthalene

The compound was prepared as in example 6 except that the compound ofexample 5 was used as substrate instead of the compound of example 4.found: C, 71.78; H, 7.37; N, 6.40. C₂₇ H₃₂ N₂ O₄.0.12 H₂ O requires C,71.95; H, 7.21; N, 6.21% ¹ H NMR (d⁶ DMSO) δ 8.8 (1H, d), 8.3 (1H, t),8.1 (1H, s), 7.8 (2H, m), 7.5 (3H, m), 4.4 (1H, m), 3.7 (3H, s), 2.9(2H, 2×dd), 1.9 (3H, s), 1.6 (6H, q), 1.5 (6H, s), 1.4 (3H, d).

EXAMPLE 9

2-(2R-carboxypyrrolidino-carbonyl)-3-(1-adamantanemethyl(N-methyl)aminocarbonyl)-naphthalene

a. 3-(1-adamantanemethyl(N-methyl)aminocarbonyl)-2-naphthoic acid

This was prepared essentially as in example 1 except thatN-methyl-1-adamantanemethylamine was used as substrate instead of1-adamantanemethylamine.

b.2-(2R-carboxypyrrolidino-carbonyl)-3-(1-adamantanemethyl(N-methyl)aminocarbonyl)-naphthalene

The compound was prepared essentially as in example 3 except that thecompound prepared in step a above was used as substrate instead of thecompound of example 1 in step a, ¹ H NMR (d⁶ -DMSO) δ 12.6 (1H, s),8.1-7.3 (6H, m), 4.3 (1H, m), 3.6-2.2 (6H, m), 2.86 and 2.84 (3H, 2×s),2.0 (2H, m), 1.8 (3H, s), 1.5 (6H, q), 1.4 (6H, s).

The material was further characterised and tested as theN-methyl-D-glucamine salt found: C, 61.17; H, 7.98; N, 5.14. C₃₆ H₅₁ N₃O₉.1.3 H₂ O.1.4 dioxan requires C, 61.19; H, 8.00; N, 5.15%

EXAMPLE 10

2-(2R-(1R-carboxyethylaminocarbonyl)pyrrolidinocarbonyl)-3-(1-adamantanemethylaminocarbonyl)-naphthalene

a.2-(2R-(1R-benzyloxycarbonylethylaminocarbonyl)-pyrrolidino-carbonyl)-3-(1-adamantanemethylaminocarbonyl)-naphthalene

The compound of example 3 (100 mg, 0.22 mmole) and PyBOP (113 mg, 0.22mmole) were taken up in dry dichloromethane (20 ml) and Hunigs base(0.115 ml, 0.66 mmole) was added. The reaction mixture was stirred underan atmosphere of dry argon for 1 h. D-alanine benzyl ester PTSA salt(76.3 mg, 0.22 mmole) was added and the mixture stirred overnight. Theorganic layer was washed with 5% potassium hydrogensuiphate (5 ml),sodium hydrogencarbonate (5 ml) and saturated brine (5 ml). It was thendried, filtered and evaporated to leave the crude title compound whichwas further purified by column chromatography (silica and ethylacetate). The title compound (119 mg, 88%) was isolated as a whitesolid.

b.2-(2R-(1R-carboxyethylaminocarbonyl)pyrrolidinocarbonyl)-3-(1-adamantanemethylaminocarbonyl)-naphthalene

The compound was prepared as in example 3 step b except that the productof step a above was used as substrate, instead of the product of example3 step a. ¹ H NMR (d⁶ -DMSO) δ 12.6 (1H, s), 8.6 (1H, m), 8.4 (1H, t),8.3-7.5 (6H, m), 4.4-3.9 (2H, m), 3.6-3.2 (4H, m), 2.9 (2H, m), 2.0 (2H,m), 1.8 (3H, s), 1.5 (6H, q), 1.4 (6H, s), 1.3 (3H, d).

The material was further characterised and tested as theN-methyl-D-glucamine salt

EXAMPLE 11

2-(2R-carboxymethylaminocarbonylpyrrolidinocarbonyl)-3-(1-adamantanemethylaminocarbonyl)-naphthalene

The compound was prepared essentially as in example 10 except that the4-toluene sulphonic acid salt of glycine benzyl ester was used assubstrate in step a instead of the 4-toluene sulphonic acid salt ofD-alanine benzyl ester ¹ H NMR (d⁶ -DMSO) δ 12.6 (1H, s), 8.6 (1H, m),8.4 (1H, t), 8.3-7.5 (6H, m), 4.4-4.2 (1H, m), 3.9-3.2 (6H, m), 2.9 (2H,m), 2.1 (2H, m) 1.8 (3H, s), 1.5 (6H, q), 1.4 (6H, s)

The material was further characterised and tested as theN-methyl-D-glucamine salt

EXAMPLE 12

2-(2R-(1R-carboxyethylaminocarbonyl)pyrrolidinocarbonyl)-3-(1-adamantanemethyl(N-methyl)aminocarbonyl)-naphthalene

The compound was prepared essentially as in example 10 except that thecompound of example 9 was used as the acidic substrate instead of thecompound of example 3 in step a ¹ NMR (d⁶ -DMSO) δ 12.8 (1H, s), 8.3-7.5(7H, m), 4.3-4.1 (2H, m), 3.6-2.7 (6H, m), 2.92 and 2.91 (3H, 2×s), 2.0(2H, m), 1.8 (3H, s), 1.5 (6H, q), 1.4 (6H, m), 1.3 (3H, d).

The material was further characterised and tested as theN-methyl-D-glucamine salt found: C, 53.90; H, 8.28; N, 6.52. C₃₉ H₅₆ N₄O₁₀.7.2 H₂ O. requires C, 53.82; H, 8.15; N, 6.44%

EXAMPLE 13

2-(2R-(1S-carboxyethylaminocarbonyl)pyrrolidinocarbonyl)-3-(1-adamantanemethyl(N-methyl)aminocarbonyl)-naphthalene

The compound was prepared essentially as in example 12 except that thePTSA salt of L alanine benzyl ester was used as the basic substrateinstead of the PTSA salt of D alanine benzyl ester in step a ¹ NMR (d⁶-DMSO) δ 12.8 (1H, s), 8.3-7.5 (7H, m), 4.3-4.1 (2H, m), 3.6-2.7 (6H,m), 2.92 and 2.91 (3H, 2×s), 2.0 (2H, m), 1.8 (3H, s), 1.5 (6H, q), 1.4(6H, m) , 1.3 (3H, 2×d)

The material was further characterised and tested as theN-methyl-D-glucamine salt found: C, 55.36; H, 7.88; N, 6.40. C₃₉ H₅₆ N₄O₁₀. 5.7 H₂ O. 0.1 dioxan requires C, 55.52; H, 8.07; N, 6.57%

EXAMPLE 14

2-(2R-carboxymethylaminocarbonylpyrrolidino-carbonyl)-3-(1-adamantanemethyl(N-methyl)aminocarbonyl)-naphthalene

The compound was prepared essentially as in example 12 except that thePTSA salt of glycine benzyl ester was used as the basic substrateinstead of the PTSA salt of D alanine benzyl ester in step a ¹ NMR (d⁶-DMSO) δ 12.7 (1H, s), 8.4-7.5 (7H, m), 4.3-4.1 (1H, m), 3.9-2.7 (8H,m), 2.92 and 2.91 (3H, 2×s), 2.0 (2H, m), 1.8 (3H, s), 1.5 (6H, q), 1.4(6H, m).

The material was further characterised and tested as theN-methyl-D-glucamine salt found: C, 51.52; H, 7.81; N, 6.29. C₃₈ H₅₄ N₄O₁₀. 8.5 H₂ O requires C, 51.84; H, 8.13; N, 6.36%

EXAMPLE 15

2-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-3-(1-adamantanemethylaminocarbonyl)-naphthalene

The compound was prepared essentially as in example 3 except that1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine(prepared as shown below) was used in step a instead of D-proline benzylester. ¹ NMR (d⁶ -DMSO) δ 13.3 (2H, s), 10.1 (1H, s), 9.0 (1H, d), 8.7(3H, m) 8.2 (2H, m), 8.0 (1H, m), 7.9 (1H, m), 7.6 (2H, m), 7.4 (1H, s),7.3 (5H, m), 4.8 (1H, m), 3.5-2.9 (4H, m), 1.8 (3H, s), 1.5 (6H, q), 1.4(6H, m).

The material was further characterised and tested as the diN-methyl-D-glucamine salt found: C, 57.02; H, 7.00; N, 5.63. C₅₄ H₇₃ N₅O₇. 3.7 H₂ O. 0.7 dioxan requires C, 57.21; H, 7.27; N, 5.87%

Preparation of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine

a. 3,5-dibenzyloxycarbonyl-nitrobenzene 5-nitro-isophthalic acid (2l.1g, 0.1 mol), thionyl chloride (80 ml) and DMF (10 drops) were stirredand heated for about 1 h until a clear solution was obtained. Excessthionyl chloride was removed by evaporation and the residual acidchloride was coevaporated with dichloromethane (2×100 ml) to remove thelast traces.

Benzyl alcohol (21.6 g, 0.2 mol) and triethylamine (30.03 g, 0.3 mol)were dissolved in dichloromethane (200 ml) and stirred at 0° under anatmosphere of dry nitrogen and a solution of the acid chloride indichloromethane (50 ml) was added dropwise over 20 min. The solution wasstirred and refluxed for 1 h, and the solution was cooled. The organiclayer was washed with water (2×100 ml), saturated sodiumhydrogencarbonate solution (100 ml) and dried over magnesium sulphate.The solution was filtered and evaporated to leave the title compound(39.1 g, 100%), ¹ H NMR (CDCl₃) δ 9.0 (3H, d), 7.5 (10H, m), 5.5 (4H,s).

b. 3,5-dibenzyloxycarbonyl-aniline

3,5-dibenzyloxycarbonyl-nitrobenzene (3.91 g, 10 mol) was dissolved inethyl acetate (50 ml) and tin(II)chloride dihydrate (11.27 g, 50 mmol)was added and the mixture stirred and heated at 70° under an atmosphereof nitrogen for 1 h. The mixture was poured carefully onto 5% sodiumhydrogencarbonate solution (200 ml) and a further aliquot of ethylacetate (100 ml) was added. After shaking the organic layer wasseparated and the aqueous layer was extracted with more ethyl acetate(50 ml). The combined organic layers were washed with brine, and dried,filtered and evaporated to leave a pale yellow solid (3.25 g, 90%), ¹ HNMR (CDCl₃) δ 8.1 (1H, d), 7.5 (12H, m), 5.4 (4H, s), 3.8 (2H, bs).

c.N-tert-butyloxycarbonyl-1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine

BOC-L-phenylalanine (8.76 g, 33 mmol) was dissolved in drydichloromethane (200 ml) and dry diisopropylethylamine (11.48 ml, 66mmol) was added followed by PyBROP (15.33 g, 33 mmol). The mixture wasstirred at room temperature for 5 min and then3,5-dibenzyloxycarbonyl-aniline (7.22 g, 20 mmol) was added. Thesolution was stirred at room temperature for a further 5 h and thesolution was then washed sequentially with 2M hydrochloric acid, water,saturated sodium hydrogencarbonate solution and water and finally dried,filtered and evaporated to leave an oil. This was purified by columnchromatography (90% dichloromethane and 10% ethyl acetate) to leave thetitle compound as a white solid (11.0 g, 90%). ¹ H NMR (d⁶ -DMSO) δ 10.5(1H, s), 8.5 (2H, s), 8.2 (1H, s), 7.3 (15H, m), 5.4 (4H, s), 4.3 (1H,m), 2.9 (2H, m), 1.3 (9H,s)

d. 1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine

N-tert-butyloxycarbonyl-1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine(8.0 g, 13 mmol) was dissolved in trifluoroacetic acid (40 ml) andstirred at room temperature for 30 min. The solvent was removed byevaporation and the residue taken up in dry dichloromethane (50 ml) andbasified with diisopropylethylamine. This solution was then used forsubsequent transformations.

EXAMPLE 16

2-(2S-(1R-carboxyethylaminocarbonylmethyl)-pyrrolidinocarbonyl)-3-(1-adamantanemethylaminocarbonyl)-naphthalene

The compound was prepared essentially as in example 3 except that2S-(1R-benzyloxycarbonyl-ethylaminocarbonylmethyl)-pyrrolidine in step ainstead of D-proline benzyl ester. ¹ NMR (d⁶ -DMSO) δ 8.5 (1H, m), 8.2(2H, m), 8.0 (3H, m), 7.6 (2H, m), 4.4-3.9 (2H, m), 3.5-2.7 (8H, m), 2.0(2H, m), 1.8 (3H, s), 1.5 (6H, q), 1.4 (6H, m), 1.2 (3H, 2×d).

The material was further characterised and tested as theN-methyl-D-glucamine salt Found: C, 70.34; H, 6.10; N, 5.36. C₄₂ H₄₃ N₃O₇. 1.0 methanol requires C, 70.39; H, 6.45; N, 5.73%

EXAMPLE 17

2-(1S-(3,5-dimethoxycarbonyl-phenylamino-carbonyl)-2-phenylethylaminocarbonyl)-3-(1-adamantanemethylaminocarbonyl)-naphthalene

The compound of example 15 (479 mg, 0.71 mmol) was dissolved in methanol(10 ml) and diazomethane solution in diethyl ether (4.74 ml 0.71 mmol)was added dropwise over 5 min. The solution was evaporated and the crudemixture separated by column chromatography (silica 7.5% methanol and92.5% dichloromethane) to give two products. The less polar material (rF0.8) (70 mg) was the title compound of this example. Found: C, 70.34; H,6.10; N, 5.36. C₄₂ H₄₃ N₃ O₇. 1.0 methanol requires C, 70.39; H, 6.45;N, 5.73% ¹ NMR (d⁶ -DMSO) δ 10.2 (1H, s), 9.0 (1H, d), 8.7 (3H, m) 8.2(2H, m), 8.0 (1H, m), 7.9 (1H, m), 7.6 (2H, m), 7.4 (1H, s), 7.3 (5H,m), 4.8 (1H.sub., m), 3.9 (6H, s), 3.5-2.9 (4H, m), 1.8 (3H, s), 1.5(6H, q), 1.4 (6H, m).

EXAMPLE 18

2-(1S-(3-methoxycarbonyl-5-carboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-3-(1-adamantanemethylaminocarbonyl)-naphthalene

The more polar material isolated from the chromatography in example 17(r_(F) 0.3) was designated the title compound of this example. ¹ NMR (d⁶-DMSO) δ 10.2 (1H, s), 9.0 (1H, d), 8.7 (1H, s), 8.6 (1H, t), 8.4 (1H,s), 8.2 (2H, m), 8.0 (1H, m), 7.9 (1H, m), 7.6 (2H, m), 7.4 (1H, s), 7.3(5H, m), 4.7 (1H, m), 3.8 (3H, s), 3.5-2.9 (4H, m), 1.8 (3H, s), 1.5(6H, q), 1.4 (6H, m).

The material was further characterised and tested as theN-methyl-D-glucamine salt Found: C, 57.31; H, 6.28; N, 4.50. C₄₈ H₅₈ N₄O₁₂. 1.8 dicloromethane. 1.9 dioxan requires C, 57.30; H, 6.43; N, 4.66%

EXAMPLE 19

(2R-carboxypyrrolidino-carbonyl)-2-(1-adamantanemethylaminocarbonylmethyl)-4,5-dichlorobenzene

a. Preparation of2-(1-adamantanemethylaminocarbonylmethyl)-4,5-dichlorobenzoic acid

The material was prepared essentially as in example 1 except that4,5-dichlorophthalic anhydride was used as substrate instead of2,3-naphthalenedicarboxylic anhydride.

b.(2R-carboxypyrrolidino-carbonyl)-2-(1-adamantanemethylaminocarbonylmethyl)-4,5-dichlorobenzene

The material was prepared essentially as in example 3 except that thecompound of step a above was used as substrate instead of the compoundof example 1 in step a ¹ H NMR (d⁶ -DMSO) δ 8.4 (1H, t), 7.9-7.4 (2H,m), 4.2 (1H, m), 3.6-2.7 (6H, m), 2.3 (2H, m), 2.0 (3H, s), 1.7 (6H, q),1.5 (6H, s).

The material was further characterised and tested as theN-methyl-D-glucamine salt found: C, 52.22; H, 7.20; N, 5.87. C₃₁ H₄₅ Cl₂N₃ O₉. 2.3 H₂ O requires C, 52.03; H, 6.98; N, 5.87%

EXAMPLE 20

1-(1-adamantanemethylaminocarbonyl)-8-naphthoic acid

The material was prepared essentially as in example 1 except that1,8-naphthalenedicarboxylic anhydride was used as substrate instead of2,3-naphthalenedicarboxylic anhydride. ¹ H NMR (d⁶ -DMSO) δ 8.5 (1H, m),8.4 (1H, t), 8.1-7.5 (5H, m), 2.9 (2H, d) , 1.9 (3H, s), 1.6 (6H, m) ,1.5 (6H, s)

The material was further characterised and tested as theN-methyl-D-glucamine salt found: C, 62.95; H, 7.26; N, 4.86. C₃₀ H₄₂ N₂O₈. H₂ O requires C, 62.48; H, 7.69; N, 4.86%

EXAMPLE 21

1/2-(1-adamantanemethylaminocarbonyl)-naphthoic acid Regioisomer 1

The material was prepared essentially as in example 1 except that1,2-naphthalenedicarboxylic anhydride was used as substrate instead of2,3-naphthalenedicarboxylic anhydride. Regioisomers were separated bycolumn chromatography (silica 10% methanol and 90% dichloromethane) Theless polar compound was designated the compound of this example ¹ H NMR(d⁶ -DMSO) δ 8.4 (1H, t), 8.1-7.5 (6H, m), 2.9 (2H, d), 1.9 (3H, s), 1.6(6H, m), 1.5 (6H, s).

The material was further characterised and tested as theN-methyl-D-glucamine salt found: C, 61.82; H, 7.74; N, 5.02. C₃₀ H₄₂ N₂O₈. 1.3 H₂ O requires C, 61.96; H, 7.72; N, 4.81%

EXAMPLE 22

1/2-(1-adamantanemethylaminocarbonyl)-naphthoic acid Regioisomer 2

The more polar regioisomer from the chromatography described in example21 was designated the compound of this example. ¹ H NMR (d⁶ -DMSO) δ 8.3(1H, t), 8.1-7.5 (6H, m), 2.9 (2H, d), 1.9 (3H, s), 1.6 (6H, m), 1.5(6H, s).

The material was further characterised and tested as theN-methyl-D-glucamine salt found: C, 60.93; H, 7.81; N, 5.00. C₃₀ H₄₂ N₂O₈. 1.75 H₂ O requires C, 61.05; H, 7.77; N, 4.75%

EXAMPLE 23

2-(1R-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-3-(1-adamantanemethylaminocarbonyl)-naphthalene

The compound was prepared essentially as in example 3 except that1R-(3,5-dibenzyloxycarbonylphenylaminocarbonyl) -2-phenyl ethylamine wasused in step a instead of D-proline benzyl ester. ¹ NMR (d⁶ -DMSO) δ13.3 (2H, s), 10.1 (1H, s), 9.0 (1H, d), 8.7 (3H, m) 8.2 (2H, m), 8.0(1H, m), 7.9 (1H, m), 7.6 (2H, m), 7.4 (1H, s), 7.3 (5H, m), 4.8 (1H,m), 3.5-2.9 (4H, m), 1.8 (3H, s), 1.5 (6H, q), 1.4 (6H, m).

The material was further characterised and tested as the diN-methyl-D-glucamine salt found: C, 57.02; H, 7.00; N, 5.63. C₅₄ H₇₃ N₅O₁₇. 3.7 H₂ O. 0.7 dioxan requires C, 57.21; H, 7.27; N, 5.87%

EXAMPLE 24

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole

a. 4-Methyl-5-nitro-phthalic acid

The compound was prepared as in Organic Synthesis collected volume 1,p.408 from 4-methyl phthalic anhydride and fuming nitric acid.

b. Dimethyl 4-methyl-5-nitro-phthalate

The compound prepared in step a (4.4 g, 20 mmol) was suspended inmethanol (100 ml) and concentrated sulphuric acid (2 ml) and theresulting suspension was heated under reflux for 48 h. After coolingdichloromethane (100 ml) was added and the organic layer was washed withsaturated sodium hydrogencarbonate solution. The aqueous layer wasre-extracted with dichloromethane (100 ml) and the combined organiclayers were washed with washed with brine and dried. The solution wasfiltered and evaporated to yield a white solid which was purified byrecrystallisation from hot methanol. The title compound was isolated aswhite needles (3.14 g, 62%).

c. Dimethyl 4-(2-N,N-dimethylaminoethylene)-5-nitro-phthalate

The dimethyl ester prepared in step c above (3.14 g, 12.4 mmol) wasdissolved in DMF (10 ml) and dimethylformamide dimethyl acetal (4.43 g,37.2 mmol) was added. The reaction mixture was heated at 150° for 6 hand then allowed to cool. The solution was diluted with ethyl acetate(500 ml) and the solution was washed with brine (6×100 ml), driedfiltered and evaporated to leave the title compound as a deep red solid(3.70 g, 97%).

d. 5, 6-Dimethoxycarbonyl-indole

The product of step c (1.50 g) was dissolved in toluene (200 ml) and 10%palladium on charcoal (150 mg) was introduced. The reaction was stirredunder an atmosphere of hydrogen at room temperature for 1 h. Thecatalyst was removed by filtration and the solvent by evaporation toleave the title compound (1.14 g).

e. Indole-5,6-dicarboxylic acid

To a stirred solution of the dimethyl ester produced in step d (1.14 g,4.9 mmol) in a 5:1 mixture of ethanol:water (12 ml) was added solidsodium hydroxide (0.49 g, 12.4 mmol). The solution was stirred at agentle reflux for 3 h. The solution was acidifed on cooling to pH2 withhydrochloric acid and then evaporated. The residue was azeotroped withethanol and then toluene and dried under vacuum. The residue was thenextracted with hot acetone (5×20 ml) and the combined extracts wereevaporated to leave the title compound (870 mg).

f. Indole-5,6-dicarboxylic acid anhydride

The product of step e (870 mg) was heated strongly with a heat gun for10 minutes under vacuum. This left the title compound (800 mg)

g. 6-(1-adamantanemethylaminocarbonyl)-indole-5-carboxylic acid

The product of step f (2.61 g, 14 mmol) was dissolved in dry THF (50 ml)and triethylamine (2.23 ml, 16 mmol) was added followed by1-adamantanemethylamine (2.5 g, 15.2 mmol). The solution was stirred atroom temperature for 1 h. The solution was reduced in volume to ca 30 mland then partitioned between 2M hydrochloric acid (30 ml) and ethylacetate (30 ml). the organic layer was dried, filtered and evaporated toleave a 3:2 mixture of regioisomers of which the title compound was themajor component.

h.5-(1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylamino-carbonyl)-indole

The material was made essentially as in example 2 using the mixture ofregioisomers isolated in step g above instead of3-(1-adamantanemethylaminocarbonyl)-2-naphthoic acid and1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine(prepared as shown in example 15) instead of L-alanine methyl esterhydrochloride. This led to a 3:2 mixture of regioisomers which wereseparated by column chromatography (silica 10% ethyl acetate and 90%dichloromethane to 20% ethyl acetate and 80% dichloromethane). The lesspolar material was designated the title compound.

i.5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole

This was prepared essentially as in example 3 step b except that thedibenzyl ester prepared in step h was used as substrate instead of3-(2R-benzyloxycarbonyl-pyrrolidinocarbonyl)-2-(1-adamantanemethylaminocarbonyl)-naphthalene,¹ H NMR (d⁶ -DMSO) δ 11.5 (1H, s), 10.2 (1H, s), 8.7 (1H, d), 8.6 (2H,s), 8.4 (1H, t), 8.2 (1H, s), 7.7 (1H, s), 7.5 (1H, s), 7.2 (6H, m), 6.5(1H, s), 4.8 (1H, m), 3.5 (1H, m), 3.0 (3H, m) , 1.8 (3H, s), 1.5 (6H,m) , 1.4 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt. found: C, 58.05; H, 6.99; N, 7.88. C₅₂ H₇₂N₆ O₁₇ H₂ O requires C, 58.31; H, 6.96; N, 7.85%

EXAMPLE 25

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

a. Benzimidazole-5,6-dicarboxylic acid

The compound was prepared from 5,6-dimethylbenzimidazole as described inJ.Org.Chem. 1987, 52, 2934.

b. Benzimidazole-5,6-dicarboxylic acid anhydride

This was prepared essentially as in example 24 step f except thatbenzimidazole-5,6-dicarboxylic acid was used as substrate instead ofindole-5,6, -dicarboxylic acid.

c. 5-(1-adamantanemethylaminocarbonyl)-benzimidazole-6-carboxylic acid

This was prepared essentially as in example 24 step g except that theproduct of step b above was used instead of the product of example 24step f.

d.5-(1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 24 step h except that5-(1-adamantanemethylaminocarbonyl)-benzimidazole-6-carboxylic acid wasused as substrate instead of6-(1-adamantanemethylaminocarbonyl)-indole-5-carboxylic acid and noseparation of regioisomers was required.

e.5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 24 step i except that thedibenzyl ester prepared in step d was used as substrate instead of theproduct of example 24 step h. ¹ H NMR (d⁶ -DMSO) δ 10.2 (1H, m), 8.9(1H, d), 8.7 (2H, s), 8.5 (1H, t), 8.4 (1H, s), 8.2 (1H, m), 7.9 (1H, brs), 7.3 (7H, m), 4.7 (1H, m), 3.5 (1H, m), 3.0 (3H, m), 1.8 (3H, s), 1.5(6H, m), 1.4 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt. found: C, 55.11; H, 7.09; N, 8.82. C₅₁ H₇₁N₇ O₁₇. 3.25 H₂ O requires C, 55.06; H, 7.02; N, 8.81%

EXAMPLE 26

6-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-5-(1-adamantanemethylaminocarbonyl)-indole

This was prepared essentially as in example 24 except that the morepolar dibenzyl ester prepared in step h was used as substrate in step iinstead of the product of example 24 step h. ¹ H NMR (d⁶ -DMSO) δ 11.5(1H, s), 10.2 (1H, s), 8.8 (1H, d), 8.6 (2H, s), 8.4 (1H, t), 8.2 (1H,s), 7.9 (1H, s), 7.5 (1H, t), 7.2-7.4 (5H, m), 7.0 (1H, s), 6.6 (1H, s),4.7 (1H, m), 3.4 and 2.9 (4H, m), 1.8 (3H, s), 1.5 (6H, m), 1.3 (6H, s)

EXAMPLE 27

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(2-fluorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleand regioisomer with substituents at positions 5 and 6 reversed

This was prepared essentially as in example 24 except that1S-(3,5-dibenzyloxycarbonyl-phenylaminocarbonyl)-2-(2-fluorophenyl)ethylaminewas used in step h instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine andthe mixture of regioisomers formed during this step were not separated.The1S-(3,5-dibenzyloxy-carbonylphenylaminocarbonyl)-2-(2-fluorophenyl)ethylaminewas prepared essentially as in example 15 steps c and d except thatBOC-L-2-fluorophenylalanine was used in step c instead ofBOC-L-phenylalanine. ¹ H NMR (d⁶ -DMSO) δ 11.5 (1H, s), 10.3 and 10.2(1H, 2×s), 8.8 (1H, m), 8.7 (2H, s), 8.5 (1H, m), 8.2 (1H, s), 7.9 and7.8 (1H, 2×s), 7.5-7.0 (6H, m), 6.6 and 6.5 (1H, 2×s), 4.8 (1H, m), 3.4and 2.9 (4H, m), 1.8 (3H, s), 1.5 (6H, m), 1.3 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 55.28; H, 7.09; N, 7.41. C₅₂ H₇₁FN₆ O₁₇. 3.33 H₂ O requires C, 55.22; H, 6.92; N, 7.43%

EXAMPLE 28

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(3-fluorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleand regioisomer with substituents at positions 5 and 6 reversed

This was prepared essentially as in example 24 except that1S-(3,5-dibenzyloxycarbonyl-phenylaminocarbonyl)-2-(3-fluorophenyl)ethylaminewas used in step h instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine andthe mixture of regioisomers formed during this step were not separated.The1S-(3,5-dibenzyloxy-carbonylphenylaminocarbonyl)-2-(3-fluorophenyl)ethylaminewas prepared essentially as in example 15 steps c and d except thatBOC-L-3-fluorophenylalanine was used in step c instead ofBOC-L-phenylalanine. ¹ H NMR (d⁶ -DMSO) δ 11.5 and 11.1 (1H, 2×s), 10.3and 10.2 (1H, 2×s), 8.8 (1H, m), 8.7 (2H, s), 8.4 (1H, m), 8.2 (1H, s),7.9 and 7.7 (1H, 2×s), 7.5-7.0 (6H, m), 6.6 and 6.5 (1H, 2×s), 4.8 (1H,m), 3.4 and 2.9 (4H, m), 2.0 and 1.8 (3H, m), 1.5 (6H, m), 1.3 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 55.80; H, 6.84; N, 7.25. C₅₂ H₇₁FN₆ O₁₇. 2.9 H₂ O requires C, 55.59; H, 6.89; N, 7.48%

EXAMPLE 29

5-(1R-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleand regioisomer with substituents at positions 5 and 6 reversed

This was prepared essentially as in example 24 except that1R-(3,5-dibenzyloxycarbonyl-phenylaminocarbonyl)-2-phenylethy lamine wasused in step h instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethyl amine andthe mixture of regioisomers formed during this step were not separated.The 1R-(3,5-dibenzyloxy-carbonylphenylamino-carbonyl)-2-phenylethylaminewas prepared essentially as in example 15 steps c and d except thatBOC-D-phenylalanine was used in step c instead of BOC-L-phenylalanine. ¹H NMR (d⁶ -DMSO) δ 11.5 (1H, s), 10.3 and 10.2 (1H, 2×s), 8.8 (1H, m),8.7 (2H, s), 8.4 (1H, m), 8.2 (1H, s), 7.9 and 7.7 (1H, 2×s), 7.5-7.0(7H, m), 6.6 and 6.5 (1H, 2×s), 4.7 (1H, m), 3.4 and 2.9 (4H, m), 1.8(3H, m), 1.5 (6H, m), 1.3 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 55.51; H, 7.29; N, 7.34. C₅₂ H₇₂N₆ O₁₇. 4.1 H₂ O requires C, 55.44; H, 7.17; N, 7.46%

EXAMPLE 30

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(4-hydroxyphenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole andregioisomer with substituents at positions 5 and 6 reversed

This was prepared essentially as in example 24 except that1S-(3,5-dibenzyloxycarbonyl-phenylaminocarbonyl)-2-(4-hydroxyphenyl)ethylamine was used in step h instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine andthe mixture of regioisomers formed during this step were not separated.The 1S-(3,5-dibenzyloxy-carbonylphenylaminocarbonyl)-2-(4-hydroxyphenyl)ethylamine was prepared essentially as in example 15 steps c andd except that BOC-L-tyrosine(O-benzyl ether) was used in step c insteadof BOC-L-phenylalanine and pentamethylbenzene and trifluoroacetic acidwere used together to remove both the BOC group and the tyrosinyl benzylprotection during the course of step d. ¹ H NMR (d⁶ -DMSO) δ 11.5 and11.4 (1H, 2×s), 10.3 and 10.2 (1H, 2×s), 9.2 (1H, br s), 8.8 (1H, m),8.7 (2H, s), 8.4 (1H, m), 8.2 (1H, s), 7.9 and 7.7 (1H, 2×s), 7.5 (1H,m), 7.2 (3H, m), 6.7 (2H, m), 6.6 and 6.5 (1H, 2×s), 4.6 (1H, m), 3.4and 2.9 (4H, m), 2.0 and 1.8 (3H, m), 1.6 (6H, m), 1.4 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 53.41; H, 6.95; N, 6.85. C₅₂ H₇₂N₆ O₁₈. 5.9 H₂ O requires C, 53.13; H, 7.19; N, 7.15%

EXAMPLE 31

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(4-aminophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleand regioisomer with substituents at positions 5 and 6 reversed

This was prepared essentially as in example 24 except that1S-(3,5-dibenzyloxycarbonyl-phenylaminocarbonyl)-2-(4-nitrophenyl)ethylamine was used in step h instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine andthe mixture of regioisomers formed during this step were not separated.The nitro group was reduced to the amino group during the finaldeprotection step. The1S-(3,5-dibenzyloxy-carbonylphenylaminocarbonyl)-2-(4-nitrophenyl)ethylaminewas prepared essentially as in example 15 steps c and d except thatBOC-L-4-nitrophenylalanine was used in step c instead ofBOC-L-phenylalanine. ¹ H NMR (d⁶ -DMSO) δ 11.5 (1H, 2×s), 10.2 and 10.1(1H, 2×s), 8.8 (1H, m), 8.7 (2H, s), 8.4 (1H, m), 8.2 (1H, s), 7.9 and7.7 (1H, 2×s), 7.5-7.0 (4H, m), 6.5 (3H, 2×s), 4.6 (1H, m), 3.2 and 2.8(4H, m), 1.8 (3H, m), 1.5 (6H, m), 1.4 (6H, s).

The compound was further characterised and tested as themono-N-methyl-D-glucamine salt found: C, 58.32; H, 6.73; N, 9.00. C₄₅H₅₆ FN₆ O₁₂. 3.0 H₂ O requires C, 58.30; H, 6.74; N, 9.06%

EXAMPLE 32

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(4-iodophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole

a. 3,5-di-t-butyloxycarbonyl-nitrobenzene

5-Nitroisophthalic acid (4.22 g, 20 mmol) was suspended indichloromethane (80 ml) and concentrated sulphuric acid (1 ml) wasadded. The solution was stirred and then saturated with isobutylene gas.The reaction vessel was stoppered and stirred at room temperatureovernight. The solution was filtered and anhydrous potassium carbonatewas added to the filtrate the solution was filtered and evsaporated andthe residue recrystallised from ethanol to leave the title compound as awhite solid (2.2 g).

b. 3,5-di-t-butyloxycarbonyl-aniline

The nitro compound prepared in step a (2.2 g, 6.8 mmol) was dissolved ina mixture of THF (50 ml) and methanol (50 ml) and 10% palladium oncharcoal (100 mg) was added. The reaction mixture was stirred under anatmosphere of hydrogen overnight. The catalyst was removed by filtrationand the title compound (1.94 g) isolated by evaporation.

c.N-(9-fluorenylmethoxycarbonyl)-1S-(3,5-di-t-butyloxycarbonylphenylaminocarbonyl)-2-(4-iodophenyl)ethylamine

FMOC-L-4-iodophenylalanine (3.85 g, 7.5 mmol) and PyBROP (3.5 g, 7.5mmol) were stirred in a mixture of dichloromethane (25 ml) anddiisopropylethylamine (2.63 ml, 15 mmol) for 5 min. A solution of3,5-di-t-butyloxycarbonylaniline (1.94 g, 6.6 mmol) in dichloromethane(15 ml) was added followed by DMAP (5 mg). The resulting solution wasstirred at room temperature overnight. The solution was washed with 2Mhydrochloric acid (2×25 ml) and brine (25 ml) dried filtered andevaporated. The residue was recrystallised from ethanol to leave thetitle compound as a white solid (1.91 g).

d.S-(3,5-di-t-butyloxycarbonylphenylaminocarbonyl)-2-(4-iodophenyl)ethylamine

The FMOC derivative produced in step c (1.7 g) was dissolved indiethylamine (20 ml) and stirred at room temperature for 2 h. Thesolution was evaporated and then the residue was purifed by columnchromatography (silica 50% dichloromethane and 50% ethyl acetate) toleave the title compound.

e.5-(1S-(3,5-di-t-butyloxycarbonylphenylaminocarbonyl)-2-(4-iodophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole

The product of step d (220 mg, 0.35 mmol) and the product of example 24step g (73 mg, 0.35 mmol) were dissolved in dry DMF (3 ml) and DCCI (73mg, 0.35 mmol), HOBT (50 mg, 0.35 mmol) and DMAP (5 mg) were added. Thesolution was stirred at room temperature for 4 h. The DCU produced wasremoved by filtration and washed with dichloromethane. The filtrate wasfurther diluted with dichloromethane and then washed with 2Mhydrochloric acid (2×10ml), brine (10 ml) and water (10 ml) before beingdried (magnesium sulphate) and evaporated to leave a mixture ofregioisomers at positions 5 and 6 of the indole ring. The regioisomerswere separated by column chromatography (silica 80% dichloromethane and20% ethyl acetate) to leave the less polar material as title compound(55 mg).

f.5-(1S-(3,5-di-carboxyphenylaminocarbonyl)-2-(4-iodophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole

The product of step e (50 mg) was dissolved in TFA (1 ml) and stirred atroom temperature for 1 h. The solution was filtered and evaporated andthe residue co-evaporated several times with diethyl ether. The residuewas triturated with ether and the solid filtered off and dried. Thetitle compound was left as a white solid. ¹ H NMR (d⁶ -DMSO) δ 11.5 (1H,s), 10.7 (1H, s), 8.8 (1H, d), 8.5 (1H, m), 8.4 (2H, s), 8.2 (1H, s),7.7 (3H, s), 7.5 (2H, m), 7.2 (2H, m), 7.0 (1H, s), 6.5 (1H, s), 4.7(1H, m), 3.4 and 2.9 (4H, m), 1.9 (3H, s), 1.5 (6H, m), 1.3 (6H, s).

EXAMPLE 33

5-(1S-(3,5-dipivaloyloxymethyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole

The compound of example 24 (331 mg, 0.5 mmol) was dissolved in DMF (2.5ml) and cesium carbonate (168 mg, 0.5 mmol) and pivaloyloxymethylchloride (0.144 ml, 1.0 mmol) were added. After 30 min at roomtemperature the reaction mixture was partitioned between ethyl acetate(30 ml) and 2M hydrochloric acid (30 ml). The organic layer was washedwith water (3×20 ml), dried (magnesium sulphate) and evaporated to leavea white foam which was purifed by column chromatography (silica 80%dichloromethane and 20% ethyl acetate) to leave the title compound,found: C, 67.29; H, 6.61; N, 6.28. C₅₀ H₅₈ N₄ O₁₁ requires C, 67.40; H,6.56; N, 6.29%, ¹ H NMR (d⁶ -DMSO) δ 11.5 (1H, s), 10.3 (1H, s), 8.8(3H, m), 8.5 (1H, t), 8.2 (1H, s), 7.7 (1H, s), 7.5 (1H, t), 7.2-7.5(5H, m), 7.2 (1H, s), 6.5 (1H, s), 6.0 (4H, m), 4.7 (1H, m), 3.4 and 2.9(4H, m), 1.8 (3H, s), 1.3-1.6 (12H, m), 1.1 (18H, s).

EXAMPLE 34

5-(1S-(3,5-dihydroxyaminocarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole

The compound of example 24 (300 mg, 0.45 mmol) was dissolved in DMF (5ml). Pentafluorophenol (184 mg, 1.0 mmol) and DCCI (206 mg, 1.0 mmol)were introduced and the mixture stirred at room temperature for 3 h. Thesolution was filtered and hydroxylamine hydrochloride (100 mg, 1.4 mmol)and triethylamine (0.2 ml) was added. The solution was stirred overnightand then evaporated. The material left was partitioned between ethylacetate and 2M hydrochloric acid. The organic layer was dried, filteredand evaporated to leave a solid which was triturated with severalportions of diethyl ether. The white solid left by this procedure wasisolated by filtration and dried. This was then recrystallised from a1:1 mixture of hexane and ethyl acetate to leave the title compound (110mg). ¹ H NMR (d⁶ -DMSO) δ 11.6 (1H, s), 11.2 (2H, br s), 10.2 (1H, s),8.8 (1H, d), 8.5 (3H, m), 8.0-7.1 (9H, m), 6.5 (1H, s), 4.7 (1H, m), 3.4and 2.9 (4H, m), 1.8 (3H, s), 1.6 (6H, m), 1.3 (6H, s).

EXAMPLE 35

5-(1S-(3,5-dimethoxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole

The compound of example 24 (155 mg, 0.23 mmol) was dissolved in methanol(5 ml). A 2M hexane solution of trimethylsilyldiazomethane in hexane (1ml) was added and left to stir for 30 min. The yellow solution wasevaporated and the residue partitioned between ethyl acetate and water.The aqueous phase was extracted with ethyl acetate and the combinedorganic extracts were dried (magnesium sulphate), filtered andevaporated. The residue was recrystallised from methanol to leave thetitle compound found: C, 66.00; H, 6.10; N, 7.91. C₄₀ H₄₂ N₄ O₇ . 1.9 H₂O requires C, 66.27; H, 6.37; N, 7.73%, ¹ H NMR (CDCl₃) δ 9.9 (1H, d),9.2 (1H, s), 8.7 (2H, d), 8.4 (1H, t), 7.5 (1H, s), 7.3 (7H, s), 6.7(1H, s), 6.4 (2H, m), 5.0 (1H, m), 3.9 (6H, s), 3.4 and 2.9 (4H, m), 1.9(3H, s), 1.6 (6H, m), 1.4 (6H, s).

EXAMPLE 36

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-N-methyl-indole

a.5-(1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-N-methyl-indole

5-(1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole,the title compound of Example 24 step h. (211 mg, 0.25 mmol) wasdissolved in dry THF (1 ml) and dry DMF (0.5 ml). The reaction mixturewas stirred under an atmosphere of dry nitrogen and sodium hydride (15mg, 0.3 mmol) was added. Hydrogen gas was evolved for about 5 min andthen methyl iodide (0.04 ml) was added. The mixture was stirred at roomtemperature for 1 h, diluted with brine (20 ml) and extracted withdichloromethane (20 ml). The organic layer was washed with brine (2×20ml), dried (magnesium sulphate) and evaporated. The residue was purifiedby column chromatography (silica 85% dichloromethane and 15% ethylacetate) to leave the title compound (90 mg).

b.5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-N-methyl-indole

This was prepared essentially as in example 3 step b except that theproduct of step a above was used as substrate instead of3-(2R-benzyloxycarbonyl-pyrrolidino-carbonyl)-2-(1-adamantanemethylaminocarbonyl)-naphthalene. ¹ H NMR (d⁶ -DMSO) δ 10.2 (1H, s), 8.8(1H, d), 8.7 (2H, s), 8.4 (1H, t), 8.2 (1H, s), 7.7 (1H, s), 7.5 (1H,d), 7.2-7.4 (5H, m), 7.1 (1H, s), 6.5 (1H, d), 4.7 (1H, m), 3.8 (3H, s),3.4 and 2.9 (4H, m), 1.8 (3H, s), 1.5 (6H.sub., m), 1.4 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 59.47; H, 7.24; N, 7.79. C₅₃ H₇₄N₆ O₁₇ requires C, 59.65; H, 6.99; N, 7.88%

EXAMPLE 37

6-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-5-(1-adamantanemethylaminocarbonyl)-N-methyl-indole

This was prepared essentially as in example 36 except that the morepolar dibenzyl ester prepared in example 24 step h was used as substratein step a instead of5-(1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole¹ H NMR (d⁶ -DMSO) δ 10.2 (1H, s), 8.7 (2H, m), 8.4 (1H, t), 8.2 (1H,s), 7.9 (1H, s), 7.5 (1H, d), 7.2-7.4 (5H, m), 6.8 (1H, s), 6.6 (1H, d),4.7 (1H, m), 3.8 (3H, s), 3.4 and 2.9 (4H, m), 1.8 (3H, s), 1.5 (6H, m),1.4 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 56.77; H, 7.22; N, 7.61. C₅₃ H₇₄N₆ O₁₇ . 3H₂ O requires C, 56.77; H, 7.19; N, 7.50%

EXAMPLE 38

5-(1S-(3,5-methoxyaminocarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleand regioisomer with substituents at positions 5 and 6 reversed

The compound was prepared essentially as in example 24 except that1S-(3,5-dimethoxycarbonylphenylaminocarbonyl)-2-phenylethylamine wasused in step h instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine,DCCI/HOBT coupling conditions were used and the mixture of regioisomersformed during this step were not separated. The1S-(3,5-dimethoxycarbonylphenylaminocarbonyl)-2-phenylethylamine wasprepared by hydrogenation of the product of example 15 steps c followedtreatment of the resulting diacid with O-methyl-hydroxamic acidhydrochloride in the presence of PyBROP and diisopropylethylamine.found: C, 61.86; H, 6.70; N, 10.83. C₄₀ H₄₄ N₆ O₇ . 3.15 H₂ O requiresC, 61.79; H, 6.52; N, 10.81% ¹ H NMR (d⁶ -DMSO) δ 11.8 (2H, br s), 11.5(1H, s), 10.3 and 10.2 (1H, 2×s), 8.8 (1H, m), 8.5 (3H, m), 8.0-7.1 (9H,m), 6.5 (1H, m), 4.7 (1H, m), 3.7 (6H, 2×s), 3.6-2.7 (4H, m), 1.8 (3H,s), 1.5 (6H, m), 1.4 (6H, s).

EXAMPLE 39

5-(1S-(3-methoxycarbonyl-5-pivaloyloxymethyloxycarbonyl-phenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleand regioisomer with substituents at positions 5 and 6 reversed

The compound was prepared essentially as in example 38 except that1S-(3-methoxycarbonyl-5-pivaloyloxymethyloxycarbonyl-phenylaminocarbonyl)-2-phenylethylaminewas used in step h instead of1S-(3,5-dimethoxycarbonylphenylaminocarbonyl)-2-phenylethylamine.1S-(3-methoxycarbonyl-5-pivaloyloxymethyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminewas prepared essentially as in example 15 step c except that3-methoxycarbonyl-5-pivaloyloxymethyloxycarbonyl-aniline was used assubstrate instead of 3,5-dibenzyloxycarbonylaniline. This in turn wasprepared by the treatment of monomethyl-5-nitroisophthalate with cesiumcarbonate and chloromethylpivalate followed by catalytic hydrogenation,found: C, 68.01; H, 6.42; N, 6.84. C₄₅ H₅₀ N₄ O₉ requires C, 68.34; H,6.37; N, 7.08% ¹ H NMR (d⁶ -DMSO) δ 11.5 (1H, s), 10.3 and 10.2 (1H,2×s), 8.8 (3H, m), 8.5 (1H, m), 8.2 (1H, s), 7.9 and 7.7 (1H, 2×s),7.5-7.0 (7H, m), 6.5 (1H, m), 5.9 (2H, s), 4.7 (1H, m), 3.9 (3H, s), 3.4and 2.7 (4H, m), 1.8 (3H, s), 1.5 (6H, m), 1.4 (6H, s), 1.1 (9H, s).

EXAMPLE 40

5-(1S-(3-methoxycarbonyl-5-carboxy-phenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleand regioisomer with substituents at positions 5 and 6 reversed

The compound of example 39 (300 mg) was treated with a saturatedsolution of ammonia in methanol (20 ml). The solution was stirred for 1h and on evaporation the residue was purified by column chromatography(silica 95% dichloromethane and 5% methanol) to leave the title compound(52 mg), ¹ H NMR (d⁶ -DMSO) δ 11.5 (1H.sub., s), 10.3 and 10.2 (1H,2×s), 8.8 (1H, m), 8.6 (2H, m), 8.5 (1H, m), 8.2 (1H, s), 7.9 and 7.7(1H, 2×s), 7.5-7.0 (7H, m), 6.7 (1H, s), 4.7 (1H, m), 3.8 (3H, s), 3.4and 2.7 (4H, m), 1.8 (3H, s), 1.5 (6H, m) , 1.4 (6H, s).

The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 60.71; H, 6.96; N, 7.89. C₄₆ H₅₇ N₅O₁₂ . 2H₂ O requires C, 60.85; H, 6.77; N. 7.71%

EXAMPLE 41

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethyl-N-methylaminocarbonyl)-indoleand regioisomer with substituents at positions 5 and 6 reversed

The material was prepared essentially as in example 24 except thatN-methyl-1-adamantanemethylamine was used in step g instead of1-adamantanemethylamine and that the regioisomers were not separated atthe end of step h, ¹ H NMR (d⁶ -DMSO) δ 11.5 and 11.3 (1H, 2×s), 10.3and 10.2 (1H, 2 ×s), 8.7 (1H, m), 8.6 (2H, m), 8.5 (1H, m), 8.2 (1H, s),7.9 and 7.8 (1H, 2×s), 7.5-7.0 (7H, m), 6.5 (1H, m), 4.7 (1H, m), 3.2(4H, m), 2.7 (3H, m), 1.8 (3H, s), 1.5 (12H, m).

The compound was further characterised and tested as thedi-N-methyl1-D-glucamine salt found: C, 59.76; H, 7.04; N, 7.68. C₅₃ H₇₄N₆ O₁₇ requires C, 59.65; H, 6.99; N, 7.88%

EXAMPLE 42

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(cycloheptanemethylaminocarbonyl)-indoleand regioisomer with substituents at positions 5 and 6 reversed

The material was prepared essentially as in example 24 except thatcycloheptanemethylamine was used in step g instead of1-adamantanemethylamine and that the regioisomers were not separated atthe end of step h, ¹ H NMR (d⁶ -DMSO) δ 11.5 (1H, s), 10.3 and 10.2 (1H,2×s), 8.7 (3H, m), 8.5 (1H, m), 8.2 (1H, s), 7.8 and 7.6 (1H, 2×s),7.5-7.0 (7H, m), 6.5 (1H, m), 4.7 (1H.sub., m), 3.2-2.7 (4H, m), 1.7-1.0(13H, m).

The compound was further characterised and tested as thedi-N-methyl1-D-glucamine salt found: C, 54.09; H, 7.17; N, 7.41. C₄₉ H₇₀N₆ O₁₇ . 4.3H₂ O requires C, 53.85; H, 7.25; N, 7.69%

EXAMPLE 43

5-(1S-(3,5-diaminophenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethyl-N-methylaminocarbonyl)-indoleand regioisomer with substituents at positions 5 and 6 reversed

a.N-tert-butyloxycarbonyl-1S-(3,5-dinitrophenylamino-carbonyl)-2-phenylethylamine

3,5-Dinitroaniline (3.44 g, 18.7 mmol) and BOC-L-phenylalanine methylester (5.24 g, 18.7 mmol) were dissolved in 1,2-dichloroethane (50 ml)and cooled to -10°. Trimethylaluminium (3.6 ml, 37.4 mmol) was added andthe mixture was allowed to warm to room temperature and stirred for 10d. 2M sodium hydroxide solution (20 ml) was added and the reactionmixture filtered through celite, washed with brine and treated withthree aliquots of magnesium sulphate, charcoal and celite. Afterevaporation, the residual material was chromatographed (silica gradient5-10% ethyl acetate and dichloromethane) and recrystallised from amixture of dichloromethane and hexane to leave the title compound as apale yellow solid (2.99 g).

b.5-(1S-(3,5-diaminophenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethyl-N-methylaminocarbonyl)-indoleand regioisomer with substituents at positions 5 and 6 reversed

The material was prepared essentially as in example 24 except that theproduct of step a above was used in step h after the BOC group had beenremoved with trifluoroacetic acid, instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine andthe mixture of regioisomers formed during this step were not separated.The amine groups were formed by the final hydrogenation step, ¹ H NMR(d⁶ -DMSO) δ 11.5 (1H, 2×s), 9.4 (1H, d), 8.5 (1H, dd), 8.3 (1H, m),7.8-6.5 (9H, m), 6.4 (2H, dd), 5.6 (1H, d), 4.7 (1H, m), 4.6 4H, br s),3.0-2.8 (4H, m), 2.7 (3H, m), 1.9 (3H, m), 1.6 (6H, m), 1.5 (6H, m).

The compound was further characterised and tested as the dihydrochloride salt found: C, 54.90; H, 6.63; N, 10.88. C₃₆ H₄₂ Cl₂ N₆O₃. 6H₂ O requires C, 55.18; H, 6.92; N, 10.73%

EXAMPLE 44

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-N-acetyl-indole

The unseparated mixture of diastereomers isolated at the end of example24 step h (251 mg, 0.3 mmol) was dissolved in DMF (0.5 ml) and 60%sodium hydride (14 mg, 0.36 mmol) was added. This was accompanied witheffervescence. To the yellow solution was added acetyl chloride (0.026ml, 0.36 mmol) and the mixture was stirred for 2 h at RT. A few drops ofwater were introduced before the whole reaction mixture was poured intowater (0.5 ml). The aqueous mixture was extracted with diethyl ether(5×5 ml) and the combined organic layers dried (magnesium sulphate). Theproduct was finally purifed by column chromatography (silica 10% ethylacetate and 90% dichloromethane) to leave the dibenzyl ester of thetitle compound (92 mg). This was converted to the title compound byhydrogenation essentially as described in example 3 step b. ¹ H NMR(d5-DMSO) δ 13.3 (2H, br s), 10.2 (1H, 2×s), 8.9 (1H, m), 8.6 (3H, m),8.1 (1H, s), 8.1-7.9 (2H, m), 7.4-7.1 (6H, m), 6.8 (1H, m), 4.7 (1H, m),3.4-2.9 (4H, m), 2.7 (3H, 2×s), 1.9 (3H, m), 1.6 (6H, m), 1.5 (6H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 56.96; H, 7.11; N, 7.44. C₅₄ H₇₄N₆ O₁₈.2.6H₂ O requires C, 56.79; H, 6.99; N, 7.36%

EXAMPLE 45

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylamino-carbonyl)-N-phenylsulphonyl-indole

The material was prepared essentially as in example 44 except thatphenylsulphonyl chloride was used instead of acetyl choride, ¹ H NMR (d⁶-DMSO) δ 13.3 (2H, br s), 10.1 (1H, 2×s), 9.2 and 8.9 (1H, 2×d), 8.7-8.6(3H, m), 8.2 (2H, s), 8.0 (2H, m), 7.9-7.1 (10H, m), 6.9 (1H, m), 4.7(1H, m), 3.5-2.9 (4H, m), 1.9 (3H, m), 1.6 (6H, m), 1.5 (6H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 55.23; H, 6.88; N, 6.72. C₅₈ H₇₆N₆ O₁₉ S.4. OH₂ O requires C, 56.07; H, 6.69; N, 6.64%

EXAMPLE 46

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(2,2-dimethylpropylaminocarbonyl)-indoleand regioisomer with substituents at positions 5 and 6 reversed

The material was prepared essentially as in example 24 except that2,2-dimethyl-propylamine was used in step g instead of1-adamantanemethylamine and that the regioisomers were not separated atthe end of step h, ¹ H NMR (d⁶ -DMSO) δ 11.5 (1H, s), 10.3 and 10.2 (1H,2×s), 8.7 (3H, m), 8.5 (1H, m), 8.2 (1H, s), 7.8 and 7.7 (1H, 2×s),7.5-7.0 (7H, m), 6.5 (1H, m) , 4.7 (1H, m) , 3.2-2.9 (4H, m) , 0.8 (9H,s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt wound: C, 53.21; H, 7.12; N, 8.08. C₄₆ H₆₆N₆ O₁₇ .3.5H₂ O requires C, 53.19; H, 7.09; N, 8.09%

EXAMPLE 47

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole

The material was prepared essentially as in example 24 except that1S-(3,5-dibenzyloxvcarbonylphenylaminocarbonyl)-ethylamine was used instep h instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine. Theless polar regioisomer after this step was taken through to the titlecompound by hydrogenation. The1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-ethylamine was preparedessentially as in example 15 steps c and d except that BOC-L-alanine wasused in step c instead of BOC-L-phenylalanine. ¹ H NMR (d⁶ -DMSO) δ 11.5(1H, s), 10.1 (1H, s) 8.7 (3H, m), 8.5 (1H, m), 8.2 (1H, s), 7.7 (1H,s), 7.6 (1H, s), 7.5 (1H, s), 6.5 (1H, s), 4.5 (1H, m), 2.9 (2 H, m),1.8 (3H, s), 1.5 (15H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt round: C, 53.04; H, 7.26; N, 8.05. C₄₆ H₆₈N₆ O₁₇ .3.6H₂ O requires C, 53.05; H, 7.27; N, 8.06%

EXAMPLE 48

6-(1S-(3,5-dicarboxyphenylaminocarbonyl)-ethylaminocarbonyl)-5-(1-adamantanemethylaminocarbonyl)-indole

The material was prepared essentially as in example 47 except that themore polar regioisomer after this step was taken through to the titlecompound by hydrogenation, ¹ H NMR (d⁶ -DMSO) δ 11.5 (1H, s), 10.2 (1H,s), 8.7 (3H, m), 8.4 (1H, m), 8.2 (1H, s), 7.9 (1H, s), 7.5(2H, m), 6.6(1H, s), 4.5 (1H, m), 2.9 (2H, m), 1.8 (3H, s), 1.5 (15H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 56.32; H, 7.27; N, 8.42. C₄₆ H₆₈N₆ O₁₇ requires C, 56.55; H, 7.02; N, 8.60%

EXAMPLE 49

5-(1S-(trans3,4-dimethoxycarbonylpyrrolidinocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleand regioisomer with substituents at positions 5 and 6 reversed

The material was prepared essentially as in example 24 except that1S-(trans 3,4-dimethoxy-carbonylpyrrolidinocarbonyl)-2-phenylethylaminewas used in step h instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethyl amine. Themixture of regioisomers was not separated and no hydrogenation wasperformed as a final step as no deprotection was required. ¹ H NMR (d⁶-DMSO) δ 11.4 (1H, m), 9.9 (0.5H, m), 8.6 (0.5H, m), 8.2 (1H, m),7.7-7.1 (8H, m), 6.5 (1H, m), 4.8 and 4.6 (1H, 2×m), 3.6 (6H s), 3.2-2.9(8H, m), 1.9 (3H, s), 1.8 (2H, t), 1.5 (6H, m), 1.4 (6H, m).

EXAMPLE 50

5-(1S-(trans3,4-dicarboxypyrrolidinocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleand regioisomer with substituents at positions 5 and 6 reversed

The material of example 49 (200 mg, 0.3 mmol) was dissolved in a 1:1mixture of methanol and water (10 ml) and lithium hydroxide (28 mg, 0.6mmol) was added. The temperature of the reaction vessel was raised to80° for two minutes and on cooling the reaction mixture was evaporatedand acidified to pH3 with 2M hydrochloric acid. The precipitatedmaterial was filtered and dried to leave the title compound (44 mg), ¹ HNMR (d⁶ -DMSO) δ 12.7 (2H, br s), 11.4 (1H, m), 8.6 (1H, m), 8.2 (1H,m), 7.7-7.1 (8H, m), 6.5 (1H, m), 4.8 (1H, m), 3.2-2.9 (8H, m), 1.9 (5H,m), 1.5 (6H, m), 1.4 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 58.27; H, 7.38; N, 8.06. C₅₀ H₇₄N₆ O₁₇ requires C, 58.24; H, 7.23; N, 8.15%

EXAMPLE 51

3-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-2-(1-adamantanemethylaminocarbonyl)-carbazole

This was prepared essentially as in example 24 except that the dimethylester of carbazole-2,3-dicarboxylic acid was used in step e instead ofthe dimethyl ester of indole-5,6-dicarboxylic acid. The carbazolesubstrate was made as in J.Chem.Res, 1990, 1919. ¹ H NMR (d⁶ -DMSO) δ13.2 (2H, br s), 11.6 (1H, s), 10.2 (1H, s), 8.8 (1H, d), 8.7 (2H, s),8.6 (1H, t), 8.2 (1H, s), 8.0 (1H, d), 7.7 (1H, s), 7.6 (1H, t), 7.5-7.3(7H, m), 7.2 (1H, t), 4.8 (1H, m), 3.4 and 3.0 (4H, m), 1.9 (3H, s), 1.5(6H, m), 1.4 (6H, s).

EXAMPLE 52

2-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-3-(1-adamantanemethylaminocarbonyl)-carbazole

This was prepared essentially as in example 26 except that the dimethylester of carbazole-2,3-dicarboxylic acid was used in step e instead ofthe dimethyl ester of indole-5,6-dicarboxylic acid. The carbazolesubstrate was made as in J.Chem.Res, 1990, 1919. ¹ H NMR (d⁶ -DMSO) δ11.7 (1H, s), 10.3 (1H, s), 9.0 (1H, d), 8.7 (2H, s), 8.5 (1H, t), 8.2(1H, m), 7.9 (1H, s), 7.6-7.3 (8H, m), 7.0 (1H, s), 4.8 (1H, m), 2.8 and2.5 (4H, m) , 1.9 (3H, s), 1.5 (6H, m) , 1.3 (6H, s).

EXAMPLE 53

3-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-2-(1-adamantanemethylaminocarbonyl)-5,7-diacetoxy-naphthalene,arbitrary assignment of regioisomers at positions 2 and 3.

This was prepared essentially as in example 24 except that5,7-diacetoxy-naphthalene-2,3-dicarboxylic acid anhydride was used instep f instead of indole-5,6-dicarboxylic acid anhydride. Thenaphthalene substrate was made in several steps fromnaphthalene-2,3-dicarboxylic acid. ¹ H NMR (d⁶ -acetone) δ 10.2 (1H, s),9.0 (2H, s), 8.6-8.1 (3H, m), 7.6-7.1 (9H, m), 5.0 (1H, m), 3.2 (4H, m),2.4 (6H, dd), 1.8 (3H, S), 1.6 (12H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 55.31; H, 6.62; N, 5.64. C₅₈ H₇₇N₅ O₂₁.4.1 H₂ O requires C, 55.54; H, 6.85; N, 5.58%

EXAMPLE 54

2-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-3-(1-adamantanemethylaminocarbonyl)-5,7-diacetoxy-naphthalene,arbitrary assignment of regioisomers at positions 2 and 3.

This was prepared essentially as in example 26 except that5,7-diacetoxy-naphthalene-2,3-dicarboxylic acid anhydride was used instep f instead of indole-5,6-dicarboxylic acid anhydride. Thenaphthalene substrate was made in several steps fromnaphthalene-2,3-dicarboxylic acid. ¹ H NMR (d⁶ -acetone) δ 10.2 (1H, s),9.0 (2H, s), 8.6-8.1 (3H, m), 7.6-7.1 (9H, m), 5.0 (1H, m), 3.2 (4H, m),2.4 (6H, m), 1.8 (3H, s), 1.6 (12H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 53.14; H, 6.75; N, 5.61. C₅₈ H₇₇N₅ O₂₁. 6.9 H₂ O requires C, 53.40 H, 7.02; N, 5.40%

EXAMPLE 55

3-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-2-(1-adamantanemethylaminocarbonyl)-5-nitronaphthaleneand its regioisomer with groups at positions 2 and 3 reversed

This was prepared essentially as in example 24 except that5-nitronaphthalene-2,3-dicarboxylic acid anhydride was used in step finstead of indole-5,6-dicarboxylic acid anhydride and no attempt wasmade to separate the regioisomers in step h. The naphthalene substratewas made in several steps from naphthalene-2,3-dicarboxylic acid. Thedeprotection of the dibenzyl ester without reduction of the nitro groupwas performed using phase transfer hydrogenation over 10% palladium oncharcoal using formic acid as a source of hydrogen. ¹ H NMR (d⁶ -DMSO) δ10.2 (1H, 2×s), 9.0 and 8.8 (1H, 2×d), 8.6-8.0 (4H, m), 7.6-7.1 (10H,m), 4.7 (1H, m), 3.2 (4H, m), 1.8 (3H, s), 1.5 (12H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 51.97; H, 6.70; N, 6.12. C₅₄ H₇₂N₆ O₁₉ .3.5 H₂ O. 3.5 HCOOH requires C, 51.80; H, 6.50; N, 6.30%

EXAMPLE 56

3-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-2-(1-adamantanemethylaminocarbonyl)-1-phenylnaphthaleneand its regioisomer with groups at positions 2 and 3 reversed

This was prepared essentially as in example 24 except that1-phenylnaphthalene-2,3-dicarboxylic acid anhydride was used in step finstead of indole-5,6-dicarboxylic acid anhydride and no attempt wasmade to separate the regioisomers in step h. The naphthalene substratewas made from 2-phenylpropiolic acid as described in J.Het.Chem., 1974,11(5), 687-90. ¹ H NMR (d⁶ -DMSO) δ 10.1 (1H, s), 9.8 (1H, d), 9.4 (2H,s), 8.2 (1H, s), 8.0-7.0 (16H, m), 4.8 (1H, m), 3.1 (2H, m), 2.4 (2H,m), 1.6 (3H, s), 1.4 (6H, m), 0.9 (6H, s).

The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 65.46; H, 6.89; N, 5.41. C₅₃ H₆₀ N₄O₁₂. 1.7 H₂ O requires C, 65.23; H, 6.55; N, 5.74%

EXAMPLE 57

3-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-2-(1-adamantanemethylaminocarbonyl)-1,2,3,4-tetrahydroisoquinoline

a.--N-tert-butyloxycarbonyl-3-(1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-1,2,3,4-tetrahydroisoquinoline

(±)-N-tert-butyloxycarbonyl-1,2,3,4-tetrahydroisoquinoline3-carboxylicacid (831 mg, 3 mmol) was suspended in dichloromethane (30 ml) anddiisopropylethylamine (1.56 ml, 9 mmol) and PyBOP (500 mg, 3 mmol) wasadded. After stirring for 5 min,1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine(prepared as indicated in example 15) (1.52 g, 3 mmol) was added. Afterstirring the mixture for 2 h the organic solution was washed with 5%potassium hydrogensulphate solution (30 ml) and brine (30 ml) and driedover magnesium sulphate. The organic solution was filtered andevaporated to leave a gum that was purified by column chromatography(silica dichloromethane 85% and ethyl acetate 15%) to leave the titlecompound (1.87 g).

b.3-(1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-1,2,3,4-tetrahydroisoquinoline

The product of step a (1.87 g) was treated with trifluoroacetic acid (20ml) for 20 min. After evaporation the material was partitioned between5% sodium hydrogencarbonate solution and ethyl acetate. The insolublewhite solid formed was filtered off and dried in vacuo (0.92 g).

c.3-(1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-2-(1-adamantanemethylaminocarbonyl)-1,2,3,4-tetrahydroisoquinoline

The product of step b (1.75 g, 2.6 mmol) was dissolved indichloromethane (40 ml) and 1-adamantanemethylisocyanate (0.6 g, 3.1mmol) was added. The solution was stirred at room temperature overnight.The solution was then washed with 2M hydrochloric acid and brine, driedand evaporated to leave a solid that was purified by recrystallisationfrom ethanol followed by column chromatography (silica dichloromethane80% and ethyl acetate 20%) to leave the title compound.

d.3-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-2-(1-adamantanemethylaminocarbonyl)-1,2,3,4-tetrahydroisoquinoline

This was prepared essentially as described in example 3 step b exceptthat the product of step c was used as substrate instead of3-(2R-benzyloxycarbonyl-pyrrolidino-carbonyl)-2-(1-adamantanemethylaminocarbonyl)-naphthalene.¹ H NMR (d⁶ -DMSO) δ 10.1 (1H, 2×s), 8.5 (2H, 2×s), 8.3 and 7.8 (1H,2×d), 8.2 (1H, s), 7.3-6.8 (9H, m), 6.5 and 6.4 (1H, 2 ×t), 4.7-4.2 (4H,m), 3.2-2.7 (6H, m), 1.8 (3H, m), 1.5 (6H, 15 m), 1.3 (6H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 57.23; H, 7.42; N, 7.61. C₅₃ H₇₆N₆ O₁₇ .2.5 H₂ O requires C, 57.13; H, 7.33; N, 7.54%

EXAMPLE 58

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-ethylaminocarbonyl)-6-(cycloheptanemethylaminocarbonyl)-indoleand regioisomer with substituents at positions 5 and 6 reversed

The material was prepared essentially as in example 42 except that1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-ethylamine was used instep h instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine andthat no attempt was made to separate the regioisomers at the end of thisstage. The 1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-ethylaminewas prepared essentially as in example 15 steps c and d except thatBOC-L-alanine was used in step c instead of BOC-L-phenylalanine. ¹ H NMR(d⁶ -DMSO) δ 11.5 (1H, s), 10.2 (1H, s), 8.7 (4H, m), 8.2 (1H, s), 7.6(3H, m), 6.5 (1H, s), 4.5 (1H, m), 3.1 (2H, m), 1.6-1.0 (16H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 54.88; H, 7.16; N, 8.98. C₄₃ H₆₆N₆ O₁₇ requires C, 55.00; H, 7.09; N, 8.95%

EXAMPLE 59

5-(1R-(3,5-dicarboxyphenylaminocarbonyl)-ethylaminocarbonyl)-6-(cycloheptanemethylaminocarbonyl)-indoleand regioisomer with substituents at positions 5 and 6 reversed

The material was prepared essentially as in example 58 except that1R-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-ethylamine was used instep h instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-ethylamine. The1R-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-ethylamine was preparedessentially as in example 15 steps c and d except that BOC-D-alanine wasused in step c instead of BOC-L-phenylalanine. ¹ H NMR (d⁶ -DMSO) δ 11.5(1H, s), 10.2 (1H, s), 8.7 (4H, m), 8.2 (1H, s), 7.6 (3H, m), 6.5 (1H,s), 4.5 (1H, m), 3.1 (2H, m), 1.6-1.0 (16H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 52.76; H, 7.24; N, 8.60. C₄₃ H₆₆N₆ O₁₇ . 2H₂ O requires C, 52.96; H, 7.24; N, 8.62%

EXAMPLE 60

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(4-hydroxyphenyl)ethylaminocarbonyl)-6-(1-adamantanemethyaminocarbonyl)-benzimidazole

This was prepared essentially as in example 25 except that1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-(4-hydroxyphenyl)ethylaminewas used in step d instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine. The1S-(3,5-dibenzyloxy-carbonylphenylaminocarbonyl)-2-(4-hydroxyphenyl)ethylaminewas prepared as outlined in example 30. ¹ H NMR (d⁶ -DMSO) δ 13.0 (3H,br s), 10.2 (1H, s), 9.3 (1H, br s), 8.8 (1H, d), 8.7 (2H, s), 8.5 (1H,t), 8.4 (1H, s), 8.2 (1H, s), 7.9 (1H, s), 7.2 (1H, s), 7.1 (2H, d), 6.7(2H, d), 4.6 (1H, m), 3.0-2.3 (4H, m), 1.8 (3H, s), 1.6 (6H, m), 1.4(6H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 56.79; H, 6.75; N, 8.98. C₅₁ H₇₁N₇ O₁₈ requires C, 57.24; H, 6.69; N, 9.16%

EXAMPLE 61

5-(1R-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 25 except that1R-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenyl-ethylamine wasused in step d instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine. The1R-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine wasprepared as outlined in example 29. ¹ H NMR (d⁶ -DMSO) δ 13.0 (3H, brs), 10.2 (1H, s), 8.9 (1H, d), 8.7 (2H, s), 8.5 (1H, t), 8.4 (1H, s),8.2 (1H, s), 7.9 (1H, s), 7.4 (5H, m), 7.1 (1H, s), 4.7 (1H, m), 3.5-2.6(4H, m), 1.8 (3H, s), 1.4 (12H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 54.96; H, 7.33; N, 8.83. C₅₁ H₇₁N₇ O₁₇ .3.5H₂ O requires C, 54.79; H, 7.04; N, 8.77%

EXAMPLE 62

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-cycloheptanemethylaminocarbonyl)-benzimidazole

The material was prepared essentially as in example 25 except thatcycloheptanemethylamine was used in step c instead of1-adamantanemethylamine, ¹ H NMR (d⁶ -DMSO) δ 13.2 (2H, br s), 12.8 (1H,br s), 10.2 (1H, s), 8.9 (1H, d), 8.7 (2H, s), 8.6 (1H, t), 8.4 (1H, s),8.2 (1H, s), 8.0 (1H, m), 7.4 (5H, m), 7.1 (1H, s), 4.7 (1H, m), 3.5-2.9(4H, m), 1.7-1.4 (13H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 56.48; H, 6.73; N, 9.40. C₄₈ H₆₉N₇ O₁₇ .requires C, 56.74; H, 6.84; N, 9.65%

EXAMPLE 63

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(2-fluorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 25 except that1S-(3,5-dibenzyloxycarbony1-phenylaminocarbonyl)-2-(2-fluorophenyl)ethylaminewas used in step d instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethyl amine. The1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-(2-fluorophenyl)ethylaminewas prepared as outlined in example 27. ¹ H NMR (d⁶ -DMSO) δ 13.0 (3H,br s), 10.2 (1H, s), 8.9 (1H, d), 8.7 (2H, s), 8.6 (1H, t), 8.4 (1H, s),8.2 (1H, s), 7.9 (1H, d), 7.4-7.2 (4H, m), 7.1 (1H, s), 4.8 (1H, m),3.6-2.9 (4H, m), 1.8 (3H, s), 1.6 (6H, m), 1.3 (6H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 55.19; H, 6.77; N, 8.66. C₅₁ H₇₀FN₇ O₁₈ requires C, 55.10; H, 6.75; N, 8.82%

EXAMPLE 64

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(4-aminophenyl)-ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared as outlined in example 31 except thatbenzimidazole-5,6-dicarboxylic acid anhydride was used as substrate instep g instead of indole-5,6-dicarboxylic acid anhydride and there wasno need to separate any regioisomers as these could not arise in thisreaction. ¹ H NMR (d⁶ -DMSO) δ 12.8 (1H, br s), 10.2 (1H, s), 8.8 (1H,d), 8.7 (2H, s), 8.5 (1H, t), 8.4 (1H, s), 8.2 (1H, s), 7.9 (1H, br s),7.3 (1H, s), 7.0 (2H, d), 6.6 (2H, d), 4.6 (1H, m), 3.3-2.8 (4H, m) ,1.9 (3H, s), 1.6 (6H, m) , 1.2 (6H, m).

The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 56.83; H, 6.49; N, 10.79. C₄₄ H₅₅ N₇O₁₂ .3.0 H₂ O requires C, 57.04; H, 6.62; N, 11.22%

EXAMPLE 65

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-5-aminopentylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleand regioisomer with substituents at positions 5 and 6 reversed

This was prepared essentially as in example 24 except that1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-5-benzyloxycarbonylaminopentylaminewas used in step h instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine andthe mixture of regioisomers formed during this step were not separated.The1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-5-benzyloxycarbonylaminopentylaminewas prepared essentially as in example 15 steps c and d except thatα-BOC-ε-Z-lysine was used in step c instead of BOC-L-phenylalanine. ¹ HNMR (d⁶ -DMSO) δ 11.5 (1H, 2×s), 10.2 (1H, 2×s), 8.8-8.2 (4H, m),7.9-7.2 (4H, m), 6.5 (1H, 2×s), 5.3 (1H, s), 5.0 (1H, s), 4.5 (1H, m),3.2 (4H, m), 2.0-1.0 (21H, m).

The compound was further characterised and tested as theN-methyl-D-glucamine salt found: C, 60.36; H, 7.02; N, 9.98. C₄₂ H₅₈ N₆O₂ requires C, 60.13; H, 6.97; N, 10.02%

EXAMPLE 66

5-(1S-(3,5-diethoxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleand regioisomer with substituents at positions 5 and 6 reversed

This was prepared essentially as in example 24 except that1S-(3,5-ethoxycarbonyl-phenylaminocarbonyl)-2-phenylethylamine was usedin step h instead of1S-(3,5-dibenzyloxy-carbonylphenylaminocarbonyl)-2-phenylethylamine andthe mixture of regioisomers formed during this step were not separated.No hydrogenation was required.1S-(3,5-ethoxycarbonyl-phenylaminocarbonyl)-2-phenylethylamine wasprepared as outlined in example 15 steps c and d except that3,5-diethoxycarbonylaniline was used in step c instead of3,5-dibenzyloxycarbonylaniline. found: C, 69.88; H, 6.59; N, 7.67. C₄₂H₄₆ N₄ O₇ requires C, 70.18; H, 6.45; N, 7.79% ¹ H NMR (d⁶ -DMSO) δ 11.5(1H, s), 10.3 and 10.2 (1H, 2×s), 8.8 (3H, m), 8.5 (1H, t), 8.2 (1H, s),7.9 and 7.7 (1H, 2×s), 7.5-7.2 (6H, m), 7.0 (1H, 2×s), 6.5 (1H, 2×s),4.7 (1H, m), 4.4 (4H, q), 3.4 and 2.9 (4H, m), 1.8 (3H, s), 1.5 (6H, m),1.4 (6H, s), 1.3 (6H, t).

EXAMPLE 67

5-(1S-(4-fluorophenylmethylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 25 except that1S-(4-fluorophenylmethylaminocarbonyl)-2-phenylethylamine was used instep d instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine andno final deprotection step was required. The1S-(4-fluorophenylmethylaminocarbonyl)-2-phenylethylamine was preparedby coupling BOC-L-phenylalanine NHS ester with 4-fluorobenzylamine inDME followed by treatment with trifluoroacetic acid. Found: C, 71.14; H,6.43; N, 11.39. C₃₆ H₃₈ FN₅ O₃ requires C, 71.15; H, 6.30; N, 11.52% ¹ HNMR (d⁶ -DMSO) δ 11.3 (1H; br s), 8.7 (2H, m), 8.5 (2H, br s), 7.8 (1H,s), 7.4-7.1 (10H, m), 4.6 (1H, m), 4.4 (2H, m), 3.4 (2H, m), 2.8 (2H,m), 1.9 (3H, s), 1.6 (6H, m), 1.4 (6H, s).

EXAMPLE 68

5-(1S-(4-fluorophenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 25 except that1S-(4-fluorophenylaminocarbonyl)-2-phenylethyl amine was used in step dinstead of 1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine and no final deprotection step was needed. The1S-(4-fluorophenylaminocarbonyl)-2-phenylethylamine was prepared bycoupling BOC-L-phenylalanine with 4-fluoroaniline using PyBrOP, followedby treatment with trifluoroacetic acid. Found: C, 70.62; H, 6.26; N,11.75. C₃₅ H₃₆ FN₅ O₃ requires C, 70.81; H, 6.11; N, 11.80% ¹ H NMR (d⁶-DMSO) δ 12.8(1H, br s), 10.0 (1H, br s), 8.8 (1H, m), 8.6 (1H, br s),8.4 (1H, s), 7.9 (3H, m), 7.8-7.1 (8H, m), 4.7 (1H, m), 3.5 (1H, m), 3.1(1H, m), 2.9 (2H, m), 1.9 (3H, s), 1.6 (12H, m).

EXAMPLE 69

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(2,4-imidazolyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 25 except that1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-(2,4-imidazolyl)ethylaminewas used in step d instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethyl amine. The1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-(2,4-imidazolyl)ethylaminewas prepared by coupling BOC-L-histidine (with the aromatic ringnitrogen protected with a BOM group) to 3,5-dibenzyloxycarbonylanilineusing PyBrOP, followed by treatment with trifluoroacetic acid. ¹ H NMR(d⁶ -DMSO) δ 10.1(1H, br s), 8.8 (1H, m), 8.6 (2H, br s), 8.5 (1H, brs), 8.4 (1H, s), 8.2 (1H, s), 7.9 (1H, s), 7.6 (1H, s), 7.5 (1H, s), 6.9(1H, s), 4.7 (1H, m), 3.2-3.0 (4H, m), 1.8 (3H, s), 1.5 (12H, m).

EXAMPLE 70

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(2-fluorophenyl)ethylaminocarbonyl)-6-(cycloheptanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 63 except thatcycloheptanemethylamine was used instead of 1-adamantanemethylamine instep c, ¹ H NMR (d⁶ -DMSO) δ 13.0 (3H, br s), 10.2 (1H, br s), 8.9 (1H,d), 8.74 (2H, s), 8.7 (1H, t), 8.4 (1H, s), 8.2 (1H, s), 7.8 (1H, s),7.5-7.1 (5H, m), 4.8 (1H, m), 3.5 (1H, m), 3.3-3.1 (3H, m), 1.6-1.1(13H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt. Found: C, 55.39; H, 6.85; N, 9.17. C₄₈ H₆₈FN₇ O₁₇ requires C, 55.75; H, 6.63; N, 9.48%

EXAMPLE 71

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 25 except that1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-ethylamine was used instep d instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine. The1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-ethylamine was preparedby coupling BOC-L-alanine to 3,5-dibenzyloxy-carbonylaniline usingPyBrOP, followed by treatment with trifluoroacetic acid. ¹ H NMR (d⁶-DMSO) δ 13.0 (3H, br s), 10.1(1H, br s), 8.8 (1H, d), 8.7 (2H, s), 8.5(1H, t), 8.4 (1H, s), 8.2 (1H, s), 7.9 (1H, s), 7.7 (1H, s), 4.5 (1H,m), 3.0 (2H, m), 1.8 (3H, s), 1.6-1.4 (15H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt. Found: C, 50.76; H, 7.23; N, 8.97. C₄₅ H₆₇N₇ O₁₇ requires C, 50.60; H, 7.27; N, 9.18%

EXAMPLE 72

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-ethylaminocarbonyl)-6-(cycloheptanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 71 except thatcycloheptanemethylamine was used instead of 1-adamantane-methylamine instep c, ¹ H NMR (d⁶ -DMSO) δ 13.0 (3H, br s), 10.2 (1H, br s), 8.8 (1H,d), 8.7 (2H, s), 8.6 (1H, t), 8.4 (1H, s), 8.2 (1H, s), 7.9 (1H, s), 7.7(1H, br s), 4.5 (1H, m) , 3.1 (2H, m) , 1.8-1.1 (16H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt. Found: C, 51.34; H, 7.29; N, 9.89. C₄₂ H₆₅FN₇ O₁₇ .2.5 H₂ O requires C, 51.25; H, 7.16; N, 9.96%

EXAMPLE 73

5-(1S-(3,5-dicarboxyphenyl-N-(methyl)amino-carbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantane-methylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 25 except that1S-(3,5-dibenzyloxycarbonylphenyl-N-(methyl)-aminocarbonyl)-2-phenylethylaminewas used in step d instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine. The1S-(3,5-dibenzyloxycarbonylphenyl-N-(methyl)-aminocarbonyl)-2-phenylethylaminewas prepared by treatment ofN-t-butyloxycarbonyl-1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminesodium hydride and methyl iodide, followed by treatment withtrifluoroacetic acid. ¹ H NMR (d⁶ -DMSO) δ 13.0 (3H, br s), 8.8 (1H, d),8.4 (2H, s), 8.0 (3H, m), 7.7 (2H, m), 7.2 (3H, m), 6.9 (2H, s), 4.5(1H, m), 3.3-2.8 (7H, m), 1.9 (3H, s), 1.6-1.4 (12H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt. Found: C, 56.43; H, 7.25; N, 8.82. C₅₂ H₇₃N₇ O₁₇ requires C, 56.27; H, 7.05; N, 8.83%

EXAMPLE 74

N-methyl-5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole,mixture of regioisomers

This was prepared essentially as in example 25 except thatN-methyl-benzimidazole-5,6-dicarboxylic acid anhydride was used in stepc instead of benzimidazole-5,6-dicarboxylic acid anhydride. This wasprepared by treatment of dimethylbenzimidazole-5,6-dicarboxylate withsodium methoxide and methyl iodide, followed by saponification withpotassium hydroxide, and anydride formation with acetic anhydride. ¹ HNMR (d⁶ -DMSO) δ 13.0 (2H, br s), 10.2 (1H, s), 8.8 (1H, m), 8.7 (2H,s), 8.6 (2H, m), 8.2 (1H, s), 8.0 and 7.9 (1H, 2×s), 7.4-7.0 (6H, m),4.8 (1H, m), 3.9 (3H, 2×s), 3.6-2.5 (4H, m), 1.8 (3H, s), 1.6-1.4 (12H,m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt. Found: C, 55.64; H, 7.15; N, 8.81. C₅₂ H₇₃N₇ O₁₇.3H₂ O requires C, 55.65; H, 7.10; N, 8.74%

EXAMPLE 75

5-(1S-(3-carboxy-4-fluoro-phenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 25 except that1S-(3-benzyloxycarbonyl-4-fluoro-phenylaminocarbonyl)-2-phenylethylaminewas used in step d instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethyl amine. The1S-(3-benzyloxycarbonyl-4-fluoro-phenylaminocarbonyl)-2-phenylethylaminewas prepared by coupling BOC-L-phenylalanine with3-benzyloxycarbonyl-4-fluoroaniline using PyBrOP, followed by treatmentwith trifluoroacetic acid. ¹ H NMR (d⁶ -DMSO) δ 13.2 (1H, br s), 12.8(1H, br s), 10.1 (1H, s), 8.8 (1H, d), 8.6 (1H, t), 8.4 (2H, m), 8.1(1H, m), 8.0 (1H, m), 7.4 (4H, s), 7.3 (2H, m), 7.1 (1H, br s), 4.5 (1H,m), 3.3-2.8 (4H, m), 1.9 (3H, s), 1.6-1.4 (12H, m).

The compound was further characterised and tested as theN-methyl-D-glucamine salt. Found: C, 59.00; H, 7.08; N, 8.55. C₄₃ H₅₃ N₆O₁₀ .2.9 H₂ O. 1.3 dioxan requires C, 56.27; H, 7.05; N, 8.83%

EXAMPLE 76

5-(2R-carboxymethylaminocarbonylpyrrolidino-carbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 25 except that2R-benzyloxycarbonylmethylaminocarbonylpyrrolidine was used in step dinstead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine. ¹ HNMR (d⁶ -DMSO) δ 12.8 (1H, br s), 12.5 (1H, br s), 8.7-7.5 (5H, m), 4.5(1H, m), 3.9 (1H, dd), 3.6 (2H, m), 3.3 (2H, m), 2.9 (1H, m), 2.1-1.5(19H, m).

The compound was further characterised and tested as theN-ethyl-D-glucamine salt. Found: C, 56.93; H, 7.42; N, 10.76. C₃₄ H₅₀ N₆O₁₀.1.4H₂ O requires C, 57.₂₅ ; H, 7.48; N, 10.43%

EXAMPLE 77

5-(2S-(3,5-dicarboxyphenylaminocarbonyl)-pyrrolidinocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 25 except that2S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-pyrrolidine was used instep d instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethyl amine. The2S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-pyrrolidine was preparedby coupling BOC-L-proline with 3,5-dibenzyloxycarbonylaniline usingPyBrOP, followed by treatment with trifluoroacetic acid. ¹ H NMR (d⁶-DMSO) δ 13.0 (3H, br s), 10.1 (1H, s), 8.7 (3H, m), 8.4 (1H, s), 8.2(1H, s), 7.6 (1H, br s), 4.6 (1H, m), 3.7-3.1 (2H, m), 3.0 (2H, d), 2.3and 2.1 (2H, m) , 1.8 (3H, s), 1.7-1.4 (12H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt. Found: C, 56.93; H, 7.42; N, 10.76. C₄₇H₆₉ N₇ O₁₇.1.4 H₂ O.requires C, 57.25; H, 7.48; N, 10.43%

EXAMPLE 78

5-(1S-(2,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 25 except that1S-(2,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethyl amine wasused in step d instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethyl amine. The1S-(2,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethyl amine wasprepared by coupling FMOC-L-phenylalanine acid chloride with2,5-dibenzyloxycarbonyl-aniline, followed by treatment with piperidine.¹ H NMR (d⁶ -DMSO) δ 13.2 (2H, br s), 11.7 (1H, br s), 9.1 (1H, d), 9.0(1H, s), 8.4 (1H, s), 8.0 (2H, m), 7.7 (3H, m), 7.4 (3H, m), 7.3 (2H,m), 7.2 (1H, m), 4.7 (1H, m), 3.4 (1H, dd), 3.1 (1H, dd), 2.8 (2H, m),1.8 (3H, s), 1.6 (6H, q), 1.4 (6H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt. Found: C, 59.00; H, 7.08; N, 8.55. C₄₃ H₅₃N₆ O₁₀. 2.9 H₂ O. 1.3 dioxan requires C, 59.03; H, 7.11; N, 8.57%

EXAMPLE 79

5-(1S-(3-carboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

a.5-(1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-benzimidazole-6-carboxylicacid

The product of example 25 step b (1.23 g, 6.5 mmol) and1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine (3.97 g,6.5 mmol) were dissolved in acetonitirile (50 ml) and stirred and heatedat reflux for 1 h. After cooling a yellow crystalline solid was formedwhich was isolated by filtration, washed with acetonitirile and dried toyield the title compound (3.65 g). The1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine had beenprepared by coupling BOC-L-phenylalanine and 3-benzyloxycarbonylanilinein the presence of PyBROP followed by treatment with trifluoroaceticacid.

b.5-(1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

The product of step a (1.12 g, 2 mmol), 4-hydroxybenzotriazole (270 mg,2 mmol), EDC (409 mg, 2 mmol), 1-adamantanemethylamine (495 mg, 3 mmol)and DMAP (20 mg) were dissolved in dry DMF (4 ml). After stirringovernight at room temperature the mixture was poured onto water (30 ml)and the resulting white precipitate was filtered and dried in vacuo toyield the title compound (1.51 g).

c.5-(1S-(3-carboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 24 step i except that thebenzyl ester prepared in step b above was used as substrate instead ofthe product of example 24 step h. ¹ H NMR (d⁶ -DMSO) δ 13.2 (2H, br s),10.1 (1H, d), 8.9 (1H, d), 8.6 (2H, m), 8.4 (1H, s), 8.1 (1H, m), 7.9(1H, s), 7.7 (1H, m), 7.4 (6H, m), 7.1 (1H, s), 4.8 (1H, m), 3.2-2.9(4H, m), 1.9 (3H, s), 1.6 (6H, q), 1.4 (6H, m).

The compound was further characterised and tested as theN-methyl-D-glucamine salt. Found: C, 60.70; H, 6.92; N, 9.89. C₄₃ H₅₄ N₆O₁₀ .2.0 H₂ O requires C, 60.69; H, 6.87; N, 9.88%

EXAMPLE 80

5-(1S-(3,5-ditetrazolylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

a. Bis pivaloyloxymethyl derivative of1S-(3,5-ditetrazolylphenylaminocarbonyl)-2-phenylethylamine

5-nitro isophthalic acid was converted to 5-nitro-3-cyanobenzonitirlevia the bis primary amide. Treatment with sodium azide in hot DMF gavethe bis tetrazole which was derivatised with POM chloride. Catalytichydrogenation of the nitro group gave the aniline, which was coupledwith BOC-L-phenylalanine using PYBROP and treated with trifluoroaceticacid to leave the title compound.

b. Bis pivaloyloxymethyl derivative of5-(1S-(3,5-ditetrazolylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 steps a and b but usingthe product of this example step a as substrate in step a instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine

c.5-(1S-(3,5-ditetrazolylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

The bis POM derivative prepared in step b (890 mg) was dissolved insaturated methanolic ammonia solution (20 ml) and stirred at roomtemperature for 5 h. The volatile material was removed by evaporation toleave the title compound (740 mg) as its bis ammonium salt, Found: C,57.36; H, 6.06; N, 27.17. C₃₇ H43N₁₅ O₃ .1.5 H₂ O requires C, 57.50; H,5.99; N, 27.18% , ¹ H NMR (d⁶ -DMSO) δ 10.2 (1H, s), 8.8 (1H, d), 8.6(2H, d), 8.4 (2H, m), 7.9 (1H, s), 7.4-7.2 (7H, m), 4.8 (1H, m), 3.5-3.0(4H, m), 1.8 (3H, s), 1.5 (6H, q), 1.4 (6H, s).

EXAMPLE 81

5-(1S-(3,5-dimethoxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantane-methylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 except that1S-(3,5-dimethoxycarbonylphenylaminocarbonyl)-2-phenylethylamine wasused in step a instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine, ¹ H NMR(d⁶ -DMSO) δ .12.8 (1H, 2×s), 10.3 and 10.2 (1H, 2×s), 8.9 (1H, t), 8.8(2H, s), 8.6 (1H, m), 8.4 (1H, s), 8.2 (1H, s), 8.0 and 7.8 (1H, 2×s),7.3 (5H, m), 7.2 and 7.1 (1H, 2×s), 4.8 (1H, m), 3.9 (6H, s), 3.4 (1H,m), 3.0 (3H, m), 1.8 (3H, s), 1.6-1.4 (12H, m).

EXAMPLE 82

5-(1S-(2-methyl-5-carboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 except that1S-(2-methyl-5-benzyloxycarbonylphenylaminocarbonyl)-2-phenyl ethylaminewas used in step a instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine,¹ H NMR(d⁶ -DMSO) δ 12.8 (2H, s), 9.7(1H, m), 8.9 (1H, m), 8.5 (1H, s), 8.4(1H.sub., s), 8.0 (1H, m) 7.7 (2H, m) 7.3 (7H, m), 4.7 (1H, m),3.4-2.7(4H, m), 2.3 (3H, s), 1.8 (3H, s), 1.6-1.4 (12H, m).

The compound was further characterised and tested as theN-methyl-D-glucamine salt. Found: C, 56.87; H, 6.89; N, 9.08. C₄₄ H₅₆ N₆O₁₀ .5.2 H₂ O requires C, 57.23; H, 7.26; N, 9.10%

EXAMPLE 83

5-(1S-(3-tetrazolylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 except that the POMderivative of 1S-(3-tetrazolylphenylaminocarbonyl)-2-phenylethylaminewas used in step a instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine. The POMderivative of 1S-(3-tetrazolylphenylaminocarbonyl)-2-phenylethylaminewas prepared essentially as in example 80 step a except that thesynthetic manipulations were carried out using the commerciallyavailable 3-nitrobenzonitrile as starting material. The compound wasisolated and tested as its ammonium salt. Found: C, 62.48; H, 6.42; N,19.72. C₃₆ H₄₀ N₁₀ O₃ .1.8 H₂ O requires C, 62.38; H, 6.34; N, 20.20% ,¹ H NMR (d⁶ -DMSO) δ 10.0 (1H, s), 8.8 (1H, d), 8.6 (1H.sub., s), 8.5(1H, t), 8.4 (1H, s), 7.9 (1H, s), 7.8 (1H, m), 7.7 (1H, d), 7.4-7.2(7H, m), 4.8 (1H, m), 3.5-2.9 (4H, m), 1.9 (3H, s), 1.5 (6H, q), 1.4(6H, s).

EXAMPLE 84

5-(1S-(3,5-ditetrazolylphenylaminocarbonyl)-2-(2-fluorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 80 except thatBOC-L-2-fluorophenylalanine was used in step a instead ofBOC-L-phenylalanine. The compound was isolated and tested as its bisammonium salt. Found: C, 54.97; H, 5.92; N, 26.06. C₃₇ H₄₂ FN₁₅ O₃ .2.5H₂ O requires C, 54.94; H, 5.85; N, 25.97% , ¹ H NMR (d⁶ -DMSO) δ 10.1(1H, s), 8.8 (1H, d), 8.4 (5H, m), 7.9 (1H, s), 7.5 (1H, t), 7.4 (1H,t), 7.3 (3H, m), 4.8 (1H, m), 3.6-2.9 (4H, m), 1.8 (3H, s), 1.5 (6H, q),1.4 (6H, s).

EXAMPLE 85

(±)-5-(1-(3,5-dicarboxyphenylaminocarbonyl)-2-(2,4-difluorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 except that(±)-1(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-(2,4-difluorophenyl)ethylaminewas used in step a instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine.(±)-1-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-(2,4-difluorophenyl)ethylaminewas prepared by coupling BOC-2,4-difluorophenylalanine with3,5-dibenzyloxycarbonylaniline using PyBrOP, followed by treatment withtrifluoroacetic acid, ¹ H NMR (d⁶ -DMSO) δ 13.2 (3H, br s), 10.2 (1H,s), 8.9 (1H, d), 8.7 (2H, d), 8.6 (1H, t), 8.4 (1H, s), 8.2 (1H, t), 7.5(1H, m), 7.3 (2H, m), 7.2 (1H, s), 7.1 (1H, m), 4.8 (1H, m), 3.5 (1H,dd), 3.0 (3H, m), 1.9 (3H, s), 1.6 (6H, q), 1.5 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt. Found: C, 52.83; H, 6.76; N, 8.26. C₅₁ H₆₉F₂ N₇ O₁₇ .4H₂ O requires C, 52.67; H, 6.68; N, 8.43%

EXAMPLE 86

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-30phenylethyl-(N-methylamino)-carbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 except that1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethyl-N-methylaminewas used in step a instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine.1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethyl-N-methylaminewas prepared by coupling BOC-N-methyl-L-phenylalanine with3,5-dibenzyloxycarbonylaniline using PyBrOP, followed by treatment withtrifluoroacetic acid.

The compound was further characterised and tested as the di-5N-methyl-D-glucamine salt. Found: C, 55.69; H, 7.04; N, 8.65. C₅₂ H₇₃ N₇O₁₇ .2H₂ O requires C, 56.56; H, 7.03; N, 8.88%

EXAMPLE 87

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(2-fluorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole

This was prepared essentially as in example 27 except that theregioisomers prepared in step h were separated and the less polarregioisomer was used as the substrate in step i. ¹ H MMR (d⁶ -DMSO) δ13.3 (2H, br s), 11.8 (1H, s), 10.2 (1H, s), 8.74 (1H, d), 8.7 (2H, s),8.5 (1H, t), 8.2 (1H, s), 7.8 (1H, s), 7.6-7.2 (6H, m), 6.5 (1H, s), 4.8(1H, m), 3.6 (1H, m), 3.0 (3H, m), 1.9 (3H, br s), 1.6 (12H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 55.55; H, 6.89; N, 7.61. C₅₂ H₇₁FN₆ O₁₇ . 2.8 H₂ O requires C, 55.67; H, 6.89; N, 7.49%

EXAMPLE 88

6-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(2-25fluorophenyl)ethylaminocarbonyl)-5-(1-adamantaneinetnyl-aminocarbonyl)-indole

This was prepared essentially as in example 27 except that theregioisomers prepared in step h were separated and the more polarregioisomer was used as the substrate in step i. ¹ H NMR (d⁶ -DMSO) δ13.3 (2H, br s), 11.5 (1H, s), 10.3 (1H, s), 8.8 (1H, d) , 8.7 (2H, s),8.4 (1H, t) , 8.2 (1H, s) , 7.9 (1H, s), 7.5-7.2 (5H, m), 7.0 (1H, s),6.6 (1H, s), 4.8 (1H, m), 3.6 (1H, m), 3.0 (3H, m), 1.8 (3H, br s), 1.6(12H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt found: C, 55.27; H, 7.03; N, 7.49. C₅₂ H₇₁FN₆ O₁₇. 3.3 H₂ O requires C, 55.22; H, 6.92; N, 7.43%

EXAMPLE 89

5-(2R-(1R-carboxyethylaminocarbonyl)pyrrolidinocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleMixture of regioisomers at positions 5 and 6

This was prepared essentially as in example 24 except that2R-(1R-benzyloxycarbonylethylaminocarbonyl)pyrrolidine was used in steph instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethyl amine. ¹ HNMR (d⁶ -DMSO) δ 11.4 (1H, 2×s), 9.0-7.0 (6H, m), 6.5 (1H, 2×s), 4.5 and4.2 (2H, 2×m), 3.6 (2H, m), 3.3 (2H, m), 2.9 (1H, m), 2.1-1.5 (20H, m).

The compound was further characterised and tested as theN-methyl-D-glucamine salt. Found: C, 54.22; H, 7.28; N, 6.48. C₃₆ H₅₃ N₅O₁₀.1.3 DCM. 2.8 dioxan requires C, 54.29; H, 7.33; N, 6.53%

EXAMPLE 90

5-(1S-(3-carboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleMixture of regioisomers at positions 5 and 6

This was prepared essentially as in example 79 except thatindole-5,6-dicarboxylic acid anhydride was used as substrate instead ofbenzimidazole-5,6-dicarboxylic acid anhydride in step a. ¹ H NMR (d⁶-DMSO) δ 11.5 (1H, br s), 10.2 and 10.1 (1H, 2×s), 8.8 (1H, m), 8.5 (2H,m), 8.1 (1H, m), 7.9 and 7.7 (1H, 2×s), 7.7-7.4 (8H, m), 7.1 and 7.0(1H, 2×s), 6.6 and 6.5 (1H, 2×s), 4.7 (1H, m), 3.5-2.9 (4H, m), 1.9 (3H,s), 1.6 (6H, q), 1.5 (6H, m).

The compound was further characterised and tested as theN-methyl-D-glucamine salt. Found: C, 61.67; H, 7.11; N, 7.90. C₄₄ H₅₅ N₅O₁₀ .2.5 H₂ O requires C, 61.52; H, 7.04; N, 8.15%

EXAMPLE 91

5-(1R-(carboxymethylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleMixture of regioisomers at positions 5 and 6

This was prepared essentially as in example 90 except that the benzylester of D-phenylalanyl-glycine was used as substrate instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine in stepa. ¹ H NMR (d⁶ -DMSO) δ 11.4 (1H, 2×s), 8.6 (1H, m), 8.5 (1H, m), 8.3(1H, m), 7.8 and 7.6 (1H, 2×s), 7.5-7.1 (7H, m), 6.6 and 6.5 (1H, 2×s),4.6 (1H, m), 3.9-2.9 (6H, m), 1.9 (3H, s), 1.6 (6H, q), 1.5 (6H, m).

The compound was further characterised and tested as the N-methyl-D-glucamine salt. Found: C, 52.75; H, 7.77; N, 7.52. C₃₉ H₅₅ N₅ O₁₀.7.5 H₂ O requires C, 52.81; H, 7.73; N, 7.89%

EXAMPLE 92

5-(1S-(3,5-di-methylsulphonylaminophenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleMixture of regioisomers at positions 5 and 6

a.1S-(3,5-di-methylsulphonylaminophenylaminocarbonyl)-2-phenylethylamine

This was prepared by in several steps by couplingBOC-L-phenylalaninemethyl ester with 3,5-dinitroaniline usingtrimethylaluminium in toluene, followed by catalytic hydrogenation toyield the bis aniline. Treatment with methanesulphonic anhydride andsubsequent deprotection with TFA gave the title compound.

b.5-(1S-(3,5-di-methylsulphonylaminophenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleMixture of regioisomers at positions 5 and 6

The title compound was prepared essentially as in example 24 step hexcept that the product of step a above was used as substrate ratherthan1S-(3,5-dibenzyloxycarbonyl-phenylaminocarbonyl)-2-phenylethylamine. ¹ HNMR (d⁶ -DMSO) δ 11.5 (1H, br s), 10.1 and 10.0 (1H, 2×s), 8.7 (1H, dd),8.3 (1H, m), 8.1-6.5 (14H, m), 4.8 (1H, m), 3.5 (6H, s), 3.5-3.0 (4H,m), 1.9 (3H, s), 1.6 (6H, q), 1.5 (6H, m).

EXAMPLE 93

5-(1S-(3,5-di-trifluoromethylsulphonylaminophenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleMixture of regioisomers at positions 5 and 6

This was prepared essentially as in example 92 except thattrifluoromethanesulphonic anhydride was used in the course of step ainstead of methanesulphonic anhydride Found: C, 51.34; H, 4.48; N, 9.49.C₃₈ H₃₈ F₆ N₆ O₇ S₂ .1.1 H₂ O requires C, 51.41 H, 4.55; N, 9.47% ¹ HNMR (d⁶ -DMSO) δ 11.5 (1H, br s), 10.1 (1H, 2×s), 8.7 (1H, m), 8.4 (1H,m), 8.1-6.5 (14H, m), 4.7 (1H, m), 3.5-2.7 (4H, m), 1.9 (3H, s), 1.6(6H, q), 1.5 (6H, m).

EXAMPLE 94

5-(1S-(3,5-di-trifluoromethylcarbonylaminophenylamino-carbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleMixture of regioisomers at positions 5 and 6

This was prepared essentially as in example 92 except thattrifluoroacetic anhydride was used in the course of step a instead ofmethanesulphonic anhydride Found: C, 54.26; H, 5.66; N, 9.29. C₄₀ H₃₈ F₆N₆ O₅ .5 H₂ O requires C, 54.13 H, 5.46; N, 9.47% ¹ H NMR (d⁶ -DMSO) δ11.5 (1H, br s), 11.4 (2H, br s), 10.2 (1H, 2×s), 8.7 (1H, m), 8.5 (1H,m), 8.1-6.5 (12H, m), 4.8 (1H, m), 3.5-2.8 (4H, m), 1.8 (3H, s), 1.6(6H, q), 1.5 (6H, m).

EXAMPLE 95

5-(1S-(3,5-di-tert-butylaminosulphonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleMixture of regioisomers at positions 5 and 6

a.1S-(3,5-di-tert-butylaminosulphonylphenylaminocarbonyl)-2-phenylethylamine

This was prepared in several steps starting with benzene-1,3-disulphonylchloride. This was nitrated with oleum in nitric acid to give the5-nitro-1,3-bis sulphonic acid derivative. This was converted to the bissulphonyl chloride compound with phosphorus pentachloride, and thenreacted with tert-butylamine to give the bis tert-butylsulphonamide.Hydrogenation, followed by coupling with Z-L-phenylalanine using PyBROP,gave the title compound as a Z-protected derivative. This was convertedto the title compound by hydrogenation.

b.5-(1S-(3,5-di-tert-butylaminosulphonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleMixture of regioisomers at positions 5 and 6

The title compound was prepared essentially as in example 24 step hexcept that the product of step a above was used as substrate ratherthan 1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine.Found: C, 54.39; H, 6.22; N, 8.07. C₄₄ H₅₆ N₆ O₇ S₂. 2 DCM. 0.3 ethylacetate requires C, 54.44 H, 6.04; N, 8.07% ¹ H NMR (d⁶ -DMSO) δ 11.4(2H, m), 8.7 (1H, m), 8.4-6.5 (15H, m), 5.4 (1H, m), 3.1-2.6 (4H, m),1.9 (3H, s), 1.6 (6H, q) , 1.5 (6H, m) , 1.1 (18H, m).

EXAMPLE 96

5-(1S-(3,5-di-aminosulphonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleMixture of regioisomers at positions 5 and 6

The compound of example 95 (30 mg, 0.36 mmol) was treated withtrifluoroacetic acid (1 ml) and allowed to stir for 24 h at roomtemperature. The solvent was removed by evaporation and theresidue wasthen azeotroped with toluene (3×1 ml). It was then taken up indichloromethane (2 ml), and the residual solid that resulted wasisolated by filtration, washed with diethyl ether and then dried toyield the title compound (21 mg), ¹ H NMR (d⁶ -DMSO) δ 11.8 (1H, br s),11.4 (2H, m), 8.7 (1H, m), 8.4-6.5 (16H, m), 4.8 (1H, m), 3.1-2.6 (4H,m), 1.9 (3H, m), 1.6 (6H, m), 1.5 (6H, m).

EXAMPLE 97

5-(1S-(3,5-ditetrazolylphenylaminocarbonyl)-2-(2-fluorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole

This was prepared essentially as in example 84 except thatindole-5,6-dicarboxylic anhydride was used in in step b instead ofbenzimidazole-5,6-dicarboxylic anhydride. After the anhydride openingstep, the mixture of regioisomers formed was separated by chromatography(silica 5% methanol and 95% dichloromethane) and the more polarregioisomer was taken through the subsequent coupling with1-adamantanemethylamine and deprotection. ¹ H NMR (d⁶ -DMSO) δ 11.5 (1H,s), 10.2 (1H, s), 8.7 (1H, d), 8.6 (2H, s), 8.4 (1H, s), 8.3(1H, t), 7.7(1H, s), 7.5-7.0 (6H, m), 6.5 (1H, s), 4.8 (1H, m), 3.6-2.9 (4H, m), 1.8(3H, s), 1.5 (6H, q), 1.4 (6H, s).

EXAMPLE 98

6-(1S-(3,5-ditetrazolylphenylaminocarbonyl)-2-(2-fluorophenyl)ethylaminocarbonyl)-5-(1-adamantanemethylaminocarbonyl)-indole

This was prepared essentially as in example 97 except that the lesspolar regioisomer following anhydride opening was used as substrate forsubsequent transformatons. ¹ H NMR (d⁶ -DMSO) δ 11.5 (1H, s), 10.3(1H.sub., s), 8.8 (1H, d), 8.6 (2H, s), 8.4 (1H, s), 8.3(1H, t), 7.9(1H, s), 7.5-7.0 (6H, m), 6.6 (1H, s), 4.8 (1H, m), 3.6-2.9 (4H, m), 1.8(3H, s), 1.5 (6H, q) , 1.4 (6H, s).

EXAMPLE 99

5-(1S-(3-trifluoroacetylaminosulphonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleMixture of regioisomers at positions 5 and 6

a.1S-(3-trifluoroacetylaminosulphonylphenylaminocarbonyl)-2-phenylethylamine

This was prepared in several steps starting withnitrobenzene-3-sulphonyl chloride. This was converted into thesulphonamide using ammonia in benzene. Trfluoroacetic anhydride was usedto introduce the trifluoroacetyl group onto the sulphonamide. Catalytichydrogenation reduced the nitro group to an amino function and thismaterial was coupled to BOC-L-phenylalananine using the PyBROP method.Removal of the BOC group was achieved with trifluoroacetic acid.

b.5-(1S-(3,5-di-tert-butylaminosulphonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indoleMixture of regioisomers at positions 5 and 6

The title compound was prepared essentially as in example 24 step hexcept that the product of step a above was used as substrate ratherthan 1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine.¹ H NMR (d⁶ -DMSO) δ 11.5 (1.5H, m), 10.5-9.8 (1.5 H, m), 8.5-7.0 (14H,m), 6.6 and 6.5 (1H, 2×s), 4.8 (1H, m), 3.5-2.9 (4H, m), 1.9 (3H, s),1.7 (6H, m), 1.5 (6H, m).

EXAMPLE 100

5-(1S-(3-tetrazolylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole

This was prepared essentially as in example 83 except that indole-5,6-dicarboxylic acid anhydride was used as substrate rather thanbenzimidazole-5,6-dicarboxylic acid anhydride. After the anhydrideopening step, the mixture of regioisomers formed was separated bychromatography (silica 5% methanol and 95% dichloromethane) and the morepolar regioisomer was taken through the subsequent coupling with1-adamantanemethylamine.

The compound was isolated and tested as its ammonium salt. Found: C,64.58; H, 6.51; N, 18.01. C₃₇ H₄₁ N₉ O₃ .1.5 H₂ O requires C, 64.71; H,6.46; N, 18.35% , ¹ H NMR (d⁶ -DMSO) δ 11.5 (1H, s), 10.1 (1H, s), 8.7(1H, d), 8.6 (1H, s), 8.5 (1H, t), 7.9 (1H, d), 7.7 (2H, s), 7.5 (1H,t), 7.4-7.2 (7H, m), 6.5 (1H, s), 4.8 (1H, m), 3.5-2.9 (4H, m), 1.9 (3H,s), 1.6 (6H, q), 1.5 (6H, s).

EXAMPLE 101

6-(1S-(3-tetrazolylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-5-(1-adamantanemethylaminocarbonyl)-indole

This was prepared essentially as in example 100 except that the lesspolar regioisomer following anhydride opening was used as substrate forsubsequent transformations. Found: C, 64.74; H, 6.46; N, 18.07. C₃₇ H₄₁N₉ O₃ . 1.5 H₂ O requires C, 64.71; H, 6.46; N, 18.35%, ¹ H NMR (d⁶-DMSO) δ 11.5 (1H, s), 10.1 (1H, s), 8.8 (1H, d), 8.6 (1H, s), 8.4 (1H,t), 7.9 (2H, m), 7.7 (1H, d), 7.5 (1H, t), 7.4-7.2 (7H, m), 6.6 (1H, s),4.8 (1H, m), 3.5-2.9 (4H, m), 1.9 (3H, s), 1.6 (6H, q), 1.5 (6H, s).

EXAMPLE 102

5-(1S-(3-trifluoromethylsulphonylaminophenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole.Mixture of regioisomers at positions 5 and 6

This was prepared essentially as in example 93 except that3-nitroaniline was used in the course of step a instead of3,5-dinitroaniline, Found: C, 61.42; H, 5.58; N, 9.65. C₃₇ H₃₈ F₃ N₅ O₅S requires C, 61.57 H, 5.31; N, 9.70% ¹ H NMR (d⁶ -DMSO) δ 11.7 (1H, brs), 11.5 (1H, s), 10.1 and 10.0 (1H, 2×s), 8.7 (1H, m), 8.5 (1H, m), 8.1(1H, m), 7.9 and 7.8 (1H, 2×s), 7.8 (1H, m), 7.5 (1H, m), 7.4 (6H, m),7.2-7.0 (2H, m), 6.6 and 6.5 (1H, 2×s), 4.7 (1H, m), 3.5-2.8 (4H, m),1.9 (3H, s), 1.7 (6H, q), 1.5 (6H, m)

EXAMPLE 103

5-(1S-(3,5-dihydroxy-N-(methyl)aminocarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole.Mixture of regioisomers at positions 5 and 6

This was prepared essentially as in example 24 except that1S-(3,5-dibenzyloxy-N-(methyl)aminocarbonyl-phenylaminocarbonyl)-2-phenylethylaminewas used in step h instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethyl amine andthe mixture of regioisomers formed during this step were not separated ¹H NMR (d⁶ -DMSO) δ 11.5 (1H, s), 10.1 (1H, s), 8.7 (1H, dd), 8.5 (1H,m), 8.2 (2H, s), 7.9 and 7.7 (1H, 2×s), 7.6-6.5 (9H, m), 6.5 (1H, s),4.7 (1H, m), 3.5-2.7 (10H, m), 1.9 (3H, s), 1.6 (6H, m), 1.5 (6H, m).

EXAMPLE 104

5-(1S-(3,5-ditetrazolylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole

This was prepared essentially as in example 97 except thatL-phenylalanine was used in step a instead of L-2-fluorophenylalanineand the regioisomers were separated immediately prior to finaldeprotection by column chromatography (silica 75% dichloromethane 25%ethyl acetate). The less polar regioisomer was converted to the compoundof this example. ¹ H NMR (d⁶ -DMSO) δ 11.5 (1H, s), 10.4 (1H, s), 8.8(3H, m), 8.5 (2H, m), 7.7 (1H, s), 7.5 (1H, t), 7.4-7.0 (6H, m), 6.5(1H, s), 4.8 (1H, m), 3.5-2.9 (4H, m), 1.8 (3H, s), 1.5 (6H, q), 1.3(6H, s).

The compound was further characterised and tested as theN-methyl-D-glucamine salt

EXAMPLE 105

6-(1S-(3,5-ditetrazolylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-5-(1-adamantanemethylaminocarbonyl)-indole

This was prepared essentially as in example 104 except that the morepolar regioisomer isolated when regioisomers were separated wasconverted to the title compound. ¹ H NMR (d⁶ -DMSO) δ 11.5 (1H, s), 10.4(1H, s), 8.8 (3H, m), 8.5 (2H, m), 7.9 (1H, s), 7.5 (1H, t), 7.4-7.0(6H, m), 6.6 (1H, s), 4.8 (1H, m), 3.6-2.9 (4H, m), 1.8 (3H, s), 1.5(6H, q), 1.3 (6H, s).

The compound was further characterised and tested as theN-methyl-D-glucamine salt

EXAMPLE 106

5-(1S-(3,5-di-(cis-4-phenyl-3,5-dioxacyclohexaneoxycarbonyl)-phenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethyl-aminocarbonyl)-indole.

The product of example 24 (100 mg, 0.15 mmol) andcis-4-phenyl-3,5-dioxacyclohexanol (54 mg, 0.3 mmol) were dissolved indichloromethane (20 ml) and DCCI (69 mg, 0.3 mmol) was added, followedby DMAP. The mixture was stirred overnight at room temperature andfiltered to remove the DCU that had formed. Evaporation, followed bycolumn chromatography (silica 50% ethyl acetate and 50% dichloromethane)followed by trituration with hexane and ethanol gave the title compoundas a colourless solid (36 mg), ¹ H NMR (d⁶ -DMSO) δ 11.5 (1H, s), 10.4(1H, s), 8.9 (2H, m), 8.8 (1H, d), 8.4 (2H, m), 7.8-6.5 (19H, m), 5.7(2H, s), 5.0 (2H, s), 4.8 (1H, m), 4.3 (8H, q), 3.5-2.8 (4H, m), 1.8(3H, s), 1.5 (6H, q), 1.4 (6H, m).

EXAMPLE 107

5-(1S-(3,5-di-(5-indanoloxycarbonyl)-phenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethyl-aminocarbonyl)-indole.

This material was prepared essentially as in example 106 except that5-indanol was used instead of cis-4-phenyl-3,5-dioxacyclohexanol. Found:C, 73.48; H, 6.22; N, 6.17. C₅₆ H₅₄ N₄ O₇ requires C, 73.52 H, 6.19; N,6.12% ,¹ H NMR (d⁶ -DMSO) δ 11.5 (1H, s), 10.3 (1H, s), 9.0 (2H, d), 8.5(1H, t), 8.4 (1H, t), 7.8 (1H, d), 7.7-6.5 (15H, m), 4.8 (1H, m),3.6-2.8 (4H, m), 2.5 (12H, m), 1.8 (3H, s), 1.5 (6H, q), 1.4 (6H, m).

EXAMPLE 108

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-azabicyclo2.2.2!oct-3-ylmethylaminocarbonyl)-indole

a.5-(1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-indole-6-carboxylicacid

Indole-5,6-dicarboxylic acid anhydride (1.87 g, 10.0 immol) and1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethyl amine(4.96 g, 9.8 mmol) were dissolved in acetonitirile (100 ml) and stirredand heated at reflux for 30 min. After cooling a yellow crystallinesolid was formed which was isolated by filtration, washed withacetonitirile and dried to yield the title compound (3.25 g). This wasmainly the regioisomer indicated in the title. The mother liquors whenevaporated yielded mainly the other regioisomer. This was not usedfurther in this example.

b.5-(1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-azabicyclo2.2.2!oct-3-ylmethylaminocarbonyl)-indole

This was prepared essentially as in example 79 step b except that theproduct of step a above was used instead of the product of example 79step a, and 1-azabicyclo 2.2.2!oct-3-ylmethylamine instead of1-adamantanemethylamine.

c.5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-azabicyclo2.2.2!oct-3-ylmethylaminocarbonyl)-indole

This was prepared essentially as in example 24 step i except that thedibenzyl ester prepared in step b above was used as substrate instead ofthe product of example 24 step h. ¹ H NMR (d⁶ -DMSO) δ 11.5 (1H, S),10.1 (1H, 2×s), 8.7 (4H, m), 8.2 (1H, m), 7.7-6.5 (9H, m), 4.8 (1H, m),3.6-2.7 (10H, m), 2.4-1.5 (6H, m).

The compound was further characterised and tested as theN-methyl-D-glucamine salt. Found: C, 55.61; H, 6.70; N, 9.40. C₄₂ H₅₂ N₆O₁₂ requires C, 55.74; H, 6.68; N, 9.29%

EXAMPLE 109

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(4-hydroxycyclohexanemethylaminocarbonyl)-indoleIsomer 1 (unknown whether hydroxy group is cis or trans to themethylaminocarbonyl group)

This was prepared essentially as in example 108 except that4-benzyloxycyclohexanemethylamine was used in step b instead of1-azabicyclo 2.2.2!oct-3-ylmethylamine and the cis and trans isomerswere separated but not assigned at the end of step b the less polarisomer being used in this example, ¹ H NMR (d⁶ -DMSO) δ 10.3 (1H, s),8.7 (3H, m), 8.5 (1H, t), 8.2 (1H, m), 7.7 (1H, s), 7.5-7.2 (7H, m), 6.5(1H, s), 4.8 (1H, m), 3.7-2.7 (5H, m), 1.5 and 1.4 (9H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt. Found: C, 53.29; H, 7.02; N, 8.12. C₄₈ H₆₈N₆ O₁₈ 8.3.l H₂ O requires C, 52.93; H, 7.03; N, 7.71%

EXAMPLE 110

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(4-hydroxycyclohexanemethylaminocarbonyl)-indole.Isomer 2 (unknown whether hydroxy group is cis or trans to themethylaminocarbonyl group)

This was prepared essentially as in example 109 except that the morepolar isomer isolated in step b was used as substrate in step c insteadof the less polar material. ¹ H NMR (d⁶ -DMSO) δ 10.2 (1H, s), 8.7 (3H,m), 8.5 (1H, t), 8.2 (1H, m), 7.7 (1H, s), 7.5 (1H, t), 7.4-7.2 (7H, m),6.5 (1H, s), 4.8 (1H, m) , 3.5-3.0 (5H, m), 1.7-1.0 (9H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt. Found: C, 51.93; H, 6.87; N, 8.01. C₄₈ H₆₈N₆ O₁₈ .4.8 H₂ O requires C, 52.28 H, 7.08; N, 7.67%

EXAMPLE 111

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-2-methylbenzimidazole

a. 2-Methyl-benzimidazole-5,6-dicarboxylic acid anhydride

This was prepared in several steps from 3,4-dimethoxycarbonylacetanilideby nitration with fuming nitric acid, followed by treatment withsulphuric acid to remove the acetyl group selectively. Catalytichydrogenation, followed by treatment with hot acetic acid gave thebenzimidazole skeleton. Saponification followed by anhydride formationby heating of the diacid gave the title compound.

b.5-(1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-2-methyl-benzimidazole-6-carboxylicacid

This was prepared essentially as in example 108 step a except that theproduct of step a above was used as substrate instead of indole-5,6-dicarboxylic acid anhydride. The isolated filtrate was the purecarboxylic acid.

c.5-(1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-2-methylbenzimidazole

This was prepared essentially as in example 108 step b except that theproduct of step b above was used as substrate instead of the product ofexample 108 step a.

d.5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethyl-aminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-2-methylbenzimidazole

This was prepared essentially as in example 108 step c except that theproduct of step c above was used as substrate instead of the product ofexample 108 step b. ¹ H NMR (d⁶ -DMSO) δ 10.2 (1H, m), 8.8 (1H, d), 8.7(2H, s), 8.5 (1H, t), 8.2 (1H, s), 7.8 (1H, br s), 7.4 (5H, m), 7.0 (1H,s), 4.8 (1H, m), 3.5 (1H, m), 3.0 (3H, m), 2.5 (3H, s), 1.8 (3H, s), 1.6(6H, m), 1.4 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt. Found: C, 55.75; H, 7.05; N, 8.62. C₅₂ H₇₃N₇ O₁₇. 3 H₂ O requires C, 55.65 H, 7.10; N, 8.74%

EXAMPLE 112

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-4-(1-adamantanemethylaminocarbonyl)-benzimidazole.Regioisomer 1 (assignment of regioisomer uncertain)

a. Benzimidazole-4,5-dicarboxylic acid anhydride

This was prepared essentially as in example 111 step a except that3,4-dimethoxycarbonyl-2-nitroaniline was used instead of3,4-dimethoxycarbonyl-6-nitroaniline and formic acid was used instead ofacetic acid in the course of formation of the second ring.3,4-dimethoxycarbonyl-2-nitroaniline was isolated as a more minorproduct during the course of the hydrogenation described in example 111step a.

b.5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-4-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as described in example 111 steps b to dexcept that benzimidazole-4,5-dicarboxylic acid anhydride was used instep b instead of benzimidazole-5,6-dicarboxylic acid anhydride. The tworegioisomers formed during the course of these reactions were separatedat the end of step c by column chromatography (silica 5% methanol and95% dichloromethane) with the less polar regioisomer being taken throughand designated as the compound of this example. ¹ H NMR (d⁶ -DMSO) δ13.0 (1H, br s), 10.5 (2H, m), 8.6 (4H, m), 8.2 (1H, s), 7.9-7.1 (7H,m), 6.6 (1H, m), 4.8 (1H, m)), 3.6-3.0 (4H, m), 1.9 (3H, s), 1.6 (12H,m)

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt. Found: C, 55.29; H, 6.98; N, 8.93. C₅₁ H₇₁N₇ O₁₇. 3 H₂ O requires C, 55.28 H, 7.00; N, 8.85%

EXAMPLE 113

4-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-5-(1-adamantanemethylaminocarbonyl)-benzimidazole.Regioisomer 2 (assignment of regioisomer uncertain)

The material was prepared essentially as in example 112 except that themore polar regioisomer isolated after chromatography was used in thefinal deprotection step, ¹ H NMR (d⁶ -DMSO) δ 13.0 (2H, br s), 10.7 and9.5 (1H, 2×s), 8.6 (4H, m), 8.2 (1H, s), 7.7 (1H, br s), 7.4 (1H, m),7.3 (6H, m), 4.8 (1H, m), 3.6 (1H, m), 3.0 (3H, m), 1.9 (3H, s), 1.6(6H, m), 1.4 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt. Found: C, 56.22; H, 7.00; N, 9.03. C₅₁ H₇₁N₇ O₁₇. 2 H₂ O requires C, 56.18 H, 6.93; N, 8.99%

EXAMPLE 114

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-2-n-butylbenzimidazole

This was prepared essentially as in example 111 except that n-pentanoicacid was used in step a instead of acetic acid, ¹ H NMR (d⁶ -DMSO) δ13.0 (3H, m), 10.2 (1H, s), 8.8 (1H, d), 8.7 (2H, s), 8.5 (1H, t), 8.2(1H, s), 7.8 (1H, br s), 7.3 (5H, m), 7.0 (1H, s), 4.8 (1H, m), 3.5-2.7(6H, m), 1.8-1.3 (19H, m), 0.9 (3H, t).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt. Found: C, 57.39; H, 7.62; N, 8.59. C₅₅ H₇₉N₇ O₁₇. 2 H₂ O requires C, 57.63 H, 7.30; N, 8.55%

EXAMPLE 115

2-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-3-(1-adamantanemethylaminocarbonyl)-5-aminonaphthalene.Regioisomer 1 (regiochemistry unnassigned)

This was prepared essentially as in example 24 steps g to i except that5-nitronaphthalene-2,3-dicarboxylic acid anhydride was used as substrateinstead of indole-5,6-dicarboxylic acid anhydride. The less polarregioisomer isolated at the penultimate stage was used to prepare thecompound of this example. The final deprotection also served to reducethe nitro group, ¹ H NMR (d⁶ -DMSO) δ 13.5 (2H, br s), 10.2 (1H, s), 8.8(1H, d), 8.7 (2H, d), 8.5 (1H, t), 8.2 (1H, d), 8.0-6.8 (10H, m), 5.7(2H, br s), 4.8 (1H, m), 3.6-2.9 (4H, m), 1.9-1.5 (15H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt. Found: C, 56.90; H, 7.14; N, 7.42. C₅₄ H₇₄N₇ O₁₇. 3.3 H₂ O requires C, 56.94 H, 7.14; N, 7.38%

EXAMPLE 116

3-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-2-(1-adamantanemethylaminocarbonyl)-5-aminonaphthalene.Regioisomer 2 (opposite regiochemistry to example 115)

This was prepared essentially as in example 115 except that the morepolar regioisomer was taken through the final step ¹ H NMR (d -DMSO) δ13.5 (2H, br s), 10.2 (1H, s), 8.9 (1H, d), 8.7 (2H, s), 8.4 (2H, m),8.2-6.8 (10H, m), 5.9 (2H, br s), 4.8 (1H, m), 3.5-2.8 (4H, m), 1.8-1.5(15H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt. Found: C, 51.21; H, 7.26; N, 6.76. C₅₄ H₇₄N₇ O₁₇. 10 H₂ O requires C, 51.51 H, 7.52 N, 6.67%

EXAMPLE 117

5-(1S-(3,5-diaminocarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 25 except that1S-(3,5-diaminocarbonyl-phenylaminocarbonyl)-2-phenylethyl amine wasused in step d instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethyl amine andno final deprotection was required, Found: C, 54.67; H, 5.72; N, 12.58.C₃₇ H₃₉ N₇ O₅. 2.2 CH₂ Cl₂ . 1.8 DMF requires C, 54.65 H, 5.76 N, 12.78%¹ H NMR (d⁶ -DMSO) δ 12.8 (1H, br s), 10.2 (1H, s), 8.8 (1H, d), 8.5(1H, t), 8.4 (2H, m), 8.1-7.9 (5H, m), 7.4-7.1 (8H, m), 4.8 (1H, m), 3.4(2H, m), 2.9 (2H, m), 1.8 (3H, s), 1.4 (6H, m), 1.3 (6H, m).

EXAMPLE 118

5-(1S-(3,5-dihydroxyiminomethylenephenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 25 except that1S-(3,5-diahydroxyiminomethylenephenylaminocarbonyl)-2-phenyl ethylaminewas used in step d instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethyl amine andno final deprotection was required, Found: C, 63.18; H, 6.18; N, 14.01.C₃₇ H₃₉ N₇ O₅ .2.3 H₂ O requires C, 63.25 H, 6.25 N, 13.95% ¹ H NMR (d⁶-DMSO) δ 12.8 (1H, br s), 11.3 (2H, s), 10.0 (1H, m) , 8.8 (1H, d) , 8.6(1H, t) , 8.4 (1H, s), 8.1 (4H, m), 7.9 (1H, m), 7.5 (1H, s), 7.3 (5H,m), 7.2 (1H, m), 4.8 (1H, m), 3.5 (1H, m), 3.1-2.8 (3H, m), 1.8 (3H, s),1.5 (6H, m), 1.4 (6H, m).

EXAMPLE 119

5-(1S-(3,5-dihydroxymethylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

a.5-(1S-(3,5-dihydroxymethylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazolediacetoxy carbonate derivative.

This was prepared essentially as example 79 except that thediacetoxycarbonate derivative of1S-(3,5-dihydroxymethylphenylaminocarbonyl)-2-phenylethylamine was usedinstead of 1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine in step a.

b.5-(1S-(3,5-dihydroxymethylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

The product of step a above (1.91 g, 2.5 mmol) was dissolved in methanol(210 ml) and was treated with a 1% solution of potassium carbonate inwater (105 ml). After stirring overnight, the methanol was removed byevaporation and the resulting solid extracted with ethyl acetate. Theorganic layer was washed with brine, dried, filtered and evaporated toleave the title compound, Found: C, 69.69; H, 6.61; N, 11.19. C₃₇ H₄₁ N₅O₈ requires C, 69.90 H, 6.50 N, 11.02% ¹ H NMR (d⁶ -DMSO) δ 12.8 (1H, brs), 9.8 (1H, s), 8.8 (1H, d), 8.5 (1H, t), 8.4 (1H, s), 7.9 (1H, m), 7.7(2H, s), 7.3 (5H, m), 7.1 (1H, s), 7.0 (1H, s), 5.2 (2H, t), 4.7 (1H,m), 4.5 (4H, d), 3.3 (2H, m), 2.9 (2H, m), 1.9 (3H, s), 1.6 (6H, m), 1.5(6H, m).

EXAMPLE 120

5-(1S-(3,5-hydrogencarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

The compound of example 119 was oxidised by treatment with oxalylchloride in DMSO and triethylamine using dichloromethane as solvent,following the Swern oxidation protocol in 45% yield, Found: C, 67.23; H,6.08; N, 10.41. C₃₇ H₃₇ N₅ O₅ . 1.7 H₂ O requires C, 67.13 H, 6.15 N,10.58% ¹ H NMR (d⁶ -DMSO) δ 12.8 (1H, br s), 10.3 (1H, s), 10.1 (2H, s),8.9 (1H, d), 8.7 (2H, s), 8.6 (1H, t), 8.4 (1H, s), 8.2 (1H, s), 7.8(1H, s), 7.4 (5H, m), 7.1 (1H, s), 4.8 (1H, m), 3.3 (2H, m), 3.0 (2H,m), 2.0 (3H, s), 1.6 (6H, m), 1.4 (6H, m).

EXAMPLE 121

5-(1S-(3,5-di-t-butylcarbonyloxymethyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzofuran.Mixture of regioisomers at positions 5 and 6

a. 3,4-dimethoxycarbonyl-2-iodophenol

The dimethyl ester of 4-hydroxyphthallic acid (4.20 g, 20 mmol), wasdissoved in triflic acid (15 g, 100 mmol), and cooled to 0° C.N-iodosuccinimide (4.5 g, 20 mmol) was added portionwise and stirred atroom temperature for 2 h. The reaction mixture was poured onto a mixtureof ice and water and the aqueous layer was extracted withdichloromethane (3×75 ml). The combined organic layers were washedsuccesively with 5% sodium bisulphite solution and brine before beingdried, filtered and evaporated, to yield the title compound 4.51 g.

b. 5,6-Dimethoxycarbonyl-2-trimethylsilyl-benzofuran

The product of step a (4.5 g, 13.4 mmol) and TMS-acetylene (1.71 g, 17.4mmol) in triethylamine (50 ml) and dioxan (80 ml) was degassed withargon for 15 min. Copper I iodide (152 mg, 0.8 mmol), was added followedby bis triphenylphosphine palladium dichloride. (564 mg, 0.8 mmol). Thereaction was stirred at 60° C overnight under an atmosphere of argon.The solvents were removed by evaporation and the resulting oil wasredissolved in dichloromethane and washed sequentially with 10% citricacid solution and brine. The organic layer was dried, filtered andevaporated and passed through a short silica column to give the titlecompound.

c. Benzofuran-5,6-dicarboxylic acid anhydride

This was prepared from the product of step b in several steps bytreatment with hydrogen fluoride/pyridine complex to remove the silicongroup, followed by saponification to generate the diacid. Anhydride ringformation occurred on heating the diacid to approximately 100° C.

d. 6-(1-adamantanemethylaminocarbonyl)-benzofuran-5-carboxylic acid.Mixture of regioisomers at positions 5 and 6

This was prepared essentially as in example 24 step g except thatbenzofuran-5,6-dicarboxylic acid anhydride was used as substrate insteadof indole-5, 6-dicarboxylic acid anhydride.

e.5-(1S-(3,5-di-t-butylcarbonyloxymethyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzofuran.Mixture of regioisomers at positions 5 and 6

This was prepared essentially as in example 24 step h except that6-(1-adamantanemethylaminocarbonyl)-benzofuran-5-carboxylic acid wasused instead of 6-(1-adamantanemethylaminocarbonyl)-indole-5-carboxylicacid and1S-(3,5-di-t-butylcarbonyloxymethyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminewas used instead of1S-(3,5-di-benzyloxy-carbonylphenylaminocarbonyl)-2-phenylethylamine. Noattempt was made to separate the regioisomers at this point, ¹ H NMR (d⁶-DMSO) δ 10.2 (1H, s), 9.0 (1H, d), 8.8 (2H, s), 8.6 (1H, t), 8.2 (2H,m), 7.9 (1H, 2×s), 7.3 (5H, m), 7.1 (2H, m), 6.0 (4H, s), 4.7 (1H, m),3.4 (2H, m), 2.9 (2H, m), 1.4-1.3 (15H, m), 1.2 (18H, s).

EXAMPLE 122

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzofuran.Mixture of regioisomers at positions 5 and 6

a.5-(1S-(3,5-di-allyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzofuran.Mixture of regioisomers at positions 5 and 6

This was prepared essentially as in example 121 except that1S-(3,5-di-allyloxycarbonylphenylaminocarbonyl)-2-phenylethyl amine wasused in step e instead of1S-(3,5-di-t-butylcarbonyloxymethyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine

b.5-(1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzofuran

The product of step a above was de-esterifeied by treatment withdiethylamine in THF in the presence of palladium tetrakistriphenylphosphine. The product was initially isolated as the bisdiethylamine salt, ¹ H NMR (d⁶ -DMSO) δ 10.2 (1H, s), 9.0 (1H, d), 8.8(2H, s), 8.4 (3H, m), 8.1 (2H, m), 7.9 (1H, 2×s), 7.4-7.1 (6H, m), 7.0(1H, m), 4.7 (1H, m), 3.4 (1H, m), 2.9 (3H, m), 1.8 (3H, s), 1.5 (6H,q), 1.3 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt. Found: C, 69.29; H, 6.05 N, 5.86. C₅₂ H₇₁N₅ O₁₈ requires C, 69.45; H, 5.97; N, 6.07%

EXAMPLE 123

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-2,3-dihydro-benzofuran.Mixture of regioisomers at positions 5 and 6

This was prepared by hydrogenation of the dibenzyl ester of the compoundof example 122 using 10% palladium on charcoal as catalyst. ¹ H NMR (d⁶-DMSO) δ 10.1 (1H, 2×s), 8.8 and 8.7 (1H, m), 8.5 (2H, m), 8.2 (2H, m),7.5-7.2 (6H, m), 6.9 (1H, m), 4.7 (1H, m), 4.6 (2H, m), 3.4 (2H, m), 3.0(4H, m), 1.8 (3H, s), 1.5 (6H, m), 1.4 (6H, s).

The compound was further characterised and tested as thedi-methyl-D-glucamine salt. Found: C, 55.84; H, 6.99; N, 6.61. C₅₂ H₇₃N₅ O₁₈ .3.0 H₂ O requires C, 56.16; H, 7.18; N, 6.30%

EXAMPLE 124

5-(1S-(3,5-dimethoxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzofuran

This was prepared by treatment of the compound of example 121 withammonia in methanol, ¹ H NMR (d⁶ -DMSO) δ 10.2 (1H, m), 8.9 (1H, m), 8.8(2H, s), 8.2 (2H, m), 8.0 (1H, s), 7.9 (2H, 2×s), 7.4-7.0 (7H, m), 4.7(6H, m), 3.9 (6H, s), 3.4-2.9 (4H, m), 1.49 (3H, s), 1.75 (6H, q), 1.4(6H, s).

EXAMPLE 125

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzothiophene.Mixture of regioisomers at positions 5 and 6

a. Benzothiophene-5,6-dicarboxylic acid anhydride

This was prepared in several steps starting from3-methyl-2-carboxy-thiophene. Esterification and allylic brominationgave a material which on treatment with the sodium salt of4-toluenesulphonic acid gave3-toluenesulphonylmethyl-2-methoxycarbonyl-thiophene. The methyl esterwas reduced with superhydride and the resulting alcohol oxidised to thealdehyde using PDC. Cycloaddition with dimethyl fumarate using potassiumt-butoxide as base gave benzothiophene-5,6-dicarboxylic acid. This wasconverted to the title compound by treatment with acetic anhydride.

b.5-(1S-(3,5-di-t-butyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzothiophene.

This was prepared essentially as in example 121 steps d and e exceptthat benzothiophene-5, 6-dicarboxylic acid anhydride was used in step dinstead of benzofuran-5,6-dicarboxylic acid anhydride and1S-(3,5-di-t-butyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine wasused in step e instead of1S-(3,5-di-t-butylcarbonyloxymethyloxycarbonylphenyl-aminocarbonyl)-2-phenylethylamine.

c.5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)benzothiophene

The product of step b was treated with trifluoroacetic acid for 2 h. Thevolatile material was removed by evaporation and the residue azeotropedseveral times with diethyl ether to leave the title compound, ¹ H NMR(d⁶ -DMSO) δ 13.2 (2H, br s), 10.2 (1H, s), 8.9 (1H, m), 8.7 (2H, m),8.4 (1H, m), 8.3 (2H, m), 8.2 (2H, m), 8.0 (1H, m), 7.5-7.0 (5H, m), 4.8(1H, m), 3.3-2.9 (4H, m), 1.8 (3H, s), 1.6 (6H, q), 1.4 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt

EXAMPLE 126

(±)-6-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-5-(1-adamantanemethylaminocarbonyl)-4,5,6,7-tetrahydro-5-aza-benzimidazole.

a.(+)-N-1,5-di-t-Butyloxycarbonyl-6-carboxy-4,5,6,7-tetrahydro-5-aza-benzimidazole

This was prepared by treatment of D/L-histidine with aqueousformaldehyde using standard Pictet-Spengler conditions. The product wastreated with BOC anhydride to give the title compound.

b(±)-N-1,5-di-t-Butyloxycarbonyl-6-(1S-(3,5-di-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-4,5,6,7-tetrahydro-5-aza-benzimidazole

This was prepared by treatment of the product of step a with oneequivalent of1S-(3,5-di-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine and1.2 equivalents of DCCI. The product was isolated by filtration,evaporation and column chromatography (silica, ethyl acetate: DCM 1:2).

c(±)-6-(1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-5-(1-adamantanemethylaminocarbonyl)-4,5,6,7-tetrahydro-5-aza-benzimidazole

This was prepared by treating the product of step b with TFA and thenwith one eqivalent of 1-adamantanemethylisocyanate in the presence ofDMAP. After stirring overnight the reaction mixture was evaporated todryness and the residue chromatographed (silica, acetone:toluene 1:2).The most polar product was the title compound.

d.(+)-6-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-5-(1-adamantanemethylaminocarbonyl)-4,5,6,7-tetrahydro-5-aza-benzimidazole.

This was prepared essentially as in example 24 step i except that thedibenzyl ester prepared above was used as substrate instead of theproduct of example 24 step h, ¹ H NMR (d⁶ -DMSO) δ 10.3 (1H, m), 8.4(2H, m), 8.2 (1H, s), 8.0-7.7 (1H, m), 7.4 (1H, m), 7.2 (6H, m), 6.5(1H, m), 5.1 (1H, m), 4.5 (1H, m), 4.2 (1H, m), 3.3-2.8 (6H, m), 1.8(3H, m), 1.6 (6H, q), 1.4 (6H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt. Found: C, 53.86; H, 7.40; N, 9.53. C₅₀ H₇₄N₈ O₁₇ .3.5 H₂ O requires C, 53.91 H, 7.28; N, 9.98%

EXAMPLE 127

5-(1S-(²-chloro-5-carboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 25 except that1S-(2-chloro-5-benzyloxycarbonylphenylaminocarbonyl)-2-phenyl ethylaminewas used in step d instead of1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-phenylethyl amine.1S-(2-chloro-5-benzyloxycarbonylphenylaminocarbonyl)-2-phenyl ethylaminewas prepared by coupling BOC-L-phenylalanine with2-chloro-5-benzyloxycarbonylaniline using PyBrOP, followed by treatmentwith trifluoroacetic acid, ¹ H NMR (d⁶ -DMSO) δ 13.2 (1H, br s), 12.8(1H, br s), 10.0 (1H, s), 8.9 (1H, d), 8.4 (2H, s), 8.2 (1H, s), 8.0-7.6(3H, m), 7.4-7.1 (6H, m), 4.8 (1H, m), 3.4 (1H, m), 2.9 (3H, m), 1.8(3H, s), 1.6 (6H, q), 1.4 (6H, s).

The compound was further characterised and tested as theN-methyl-D-glucamine salt. Found: C, 58.33; H, 6.49; N, 9.09. C₄₃ H₅₃ClN₆ O₁₀ .2.3 H₂ O requires C, 58.01 H, 6.51; N, 9.44%

EXAMPLE 128

5-(1S-(3-trifluoroacetylaminosulphonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 99 except that the productof example 25 step c was used in step b instead of the product ofexample 24 step g, Found: C, 55.01; H, 5.27; N, 10.33. C₃₇ H₃₇ F₃ N₆ O₆S .2.3 H₂ O requires C, 58.01 H, 6.51; N, 9.44% ¹ H NMR (d⁶ -DMSO) δ10.1 (1H, s), 8.9 (1H, d), 8.5 (5H, m), 8.0-7.0 (10H, m), 4.8 (1H, m),3.6-2.9 (4H, m), 1.9 (3H, s), 1.6 (6H, m), 1.5 (6H, m).

EXAMPLE 129

5-(3S-(3,5-dicarboxyphenylaminocarbonyl)-1,2,3,4-tetrahydroisoquinolino-2-carbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 except that3S-(3,5-dibenzyloxyphenylaminocarbonyl)-1,2,3,4-tetrahydroisoquinolinewas used as substrate instead of1S-(3-benzyloxycarbonylphenyl-aminocarbonyl)-2-phenylethylamine in stepa. The3S-(3,5-dibenzyloxyphenylaminocarbonyl)-1,2,3,4-tetrahydroisoquinolinewas prepared by coupling BOC-3S-carboxy-1,2,3,4-tetrahydroisoquinolineand 3,5-dibenzyloxycarbonylaniline in the presence of PyBROP, followedby treatment with trifluoroacetic acid, ¹ H NMR (d⁶ -DMSO) δ 13.0 (3H,br s), 11.5 and 10.0 (1H, 2×s), 9.0-7.0 (11H, m), 5.4 (1H, m), 4.8-4.2(2H, m), 3.5-2.8 (4H, m), 1.9 (3H, m), 1.5 (6H, m), 1.4 (6H, m)

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt. Found: C, 55.51; H, 6.89 N, 8.80. C₅₂ H₇₁N₇ O₁₇ .3.2 H₂ O requires C, 55.58 H, 6.94; N, 8.73%

EXAMPLE 130

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(2-naphthalenenemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 except that1S-(3,5-di-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine wasused in step a instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine and2-naphthalenemethylamine was used in step b instead of1-adamantanemethylamine, ¹ H NMR (d⁶ -DMSO) δ 12.9 (1H, br s), 10.1 (1H,s), 9.3 (1H, t), 8.9 (1H, d), 8.7 (2H, s), 8.4 (2H, s), 8.1 (1H, s), 8.0(1H, m), 7.7 (4H, m), 7.4 (8H, m), 4.8 (3H, m), 3.0 (2H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt. Found: C, 54.92; H, 6.35 N, 8.95. C₅₁ H₆₃N₇ O₁₇ .3.7 H₂ O requires C, 55.06 H, 6.38; N, 8.81%

EXAMPLE 131

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(3-fluorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 except that1S-(3,5-di-benzyloxycarbonylphenylaminocarbonyl)-2-(3-fluorophenyl)ethylaminewas used in step a instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine. The1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-(3-fluorophenyl)ethylaminewas prepared by coupling BOC-L-3-fluorophenylalanine and3,5-dibenzyloxycarbonylaniline in the presence of PyBROP, followed bytreatment with trifluoroacetic acid, ¹ H NMR (d⁶ -DMSO) δ 13.0 (3H, brs), 10.2 (1H, s), 8.9 (1H, d), 8.7 (2H, s), 8.5 (1H, t), 8.4 (1H, s),8.2 (1H, s), 7.9 (1H, s), 7.4 (1H, m), 7.2 (4H, m), 4.8 (1H, m), 3.6-2.9(4H, m), 1.8 (3H, S), 1.7 (6H, q), 1.5 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt

EXAMPLE 132

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(4-fluorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 except that1S-(3,5-di-benzyloxycarbonylphenylaminocarbonyl)-2-(4-fluorophenyl)ethylaminewas used in step a instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2 -phenylethylamine. The1S-(3,5-di-benzyloxycarbonylphenylaminocarbonyl)-2-(4-fluorophenyl)ethylaminewas prepared by coupling BOC-L-4-fluorophenylalanine and3,5-dibenzyloxycarbonylaniline in the presence of PyBROP, followed bytreatment with trifluoroacetic acid, ¹ H NMR (d⁶ -DMSO) δ 13.0 (3H, brs), 10.2 (1H, s), 8.9 (1H, d), 8.7 (2H, s), 8.5 (1H, t), 8.4 (1H, s),8.2 (1H, s), 7.9 (1H, s), 7.4 (2H, m), 7.2 (3H, m), 4.8 (1H, m), 3.6-2.9(4H, m), 1.8 (3H, s), 1.7 (6H, q), 1.5 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt

EXAMPLE 133

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(2-trifluoromethylphenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 except that1S-(3,5-di-benzyloxycarbonylphenylaminocarbonyl)-2-(2-trifluoromethylphenyl)ethylaminewas used in step a instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine. The1S-(3,5-di-benzyloxycarbonylphenylaminocarbonyl)-2-(2-trifluoromethyl-phenyl)-ethylaminewas prepared by coupling BOC-L-2-trifluoromethylphenylalanine and3,5-dibenzyloxycarbonylaniline in the presence of PyBROP, followed bytreatment with trifluoroacetic acid, ¹ H NMR (d⁶ -DMSO) δ 13.0 (3H, brs), 10.2 (1H, s), 9.0 (1H, d), 8.7 (2H, s), 8.6 (1H, t), 8.4 (1H, s),8.2 (1H, s), 7.9 (1H, s), 7.7 (4H, m), 7.2 (1H, m), 4.9 (1H, m), 3.8-3.0(4H, m), 1.8 (3H, s), 1.6 (6H, q), 1.5 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt Found: C, 52.67; H, 6.57; N, 8.25. C₅₂ H₇₀F₃ N₇ O₁₇ .3.5 H₂ O requires C, 52.70 H, 6.55; N, 8.27%

EXAMPLE 134

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(4-iodophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

a5-(1S-(3,5-di-allyloxyphenylaminocarbonyl)-2-(4-iodophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 steps a and b except that1S-(3,5-di-allyloxycarbonylphenylaminocarbonyl)-2-(4-iodophenyl)ethylaminewas used in step a instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine. The1S-(3,5-di-allyloxycarbonylphenylaminocarbonyl)-2-(4-iodophenyl)ethylaminewas prepared by coupling BOC-L-4-iodophenylalanine and3,5-diallyloxycarbonylaniline in the presence of PYBROP, followed bytreatment with trifluoroacetic acid.

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(4-iodo-phenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 122 step b but using theproduct of step a above as substrate instead of5-(1S-(3,5-di-allyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzofuran.The compound was isolated and characterised as a bis dietylamine salt ¹H NMR (d⁶ -DMSO) δ 10.1 (1H, s), 8.8 (1H, d), 8.4 (4H, s), 8.2 (1H, s),7.9 (1H, s), 7.7 (2H, m), 7.3 (1H, m), 7.2 (2H, m), 4.7 (1H, m), 3.5-2.9(4H, m), 1.8 (3H, s), 1.7 (6H, q), 1.5 (6H, s).

EXAMPLE 135

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(2-chlorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 134 except that1S-(3,5-di-allyloxycarbonylphenylaminocarbonyl)-2-(2-chloro-phenyl)ethylamineinstead of1S-(3,5-di-allyloxycarbonylphenylaminocarbonyl)-2-(4-iodophenyl)ethylaminein step a. The1S-(3,5-di-allyloxycarbonylphenylaminocarbonyl)-2-(2-chlorophenyl)ethylaminewas prepared by coupling BOC-L-2-chlorophenylalanine and3,5-diallyloxycarbonylaniline in the presence of PyBROP, followed bytreatment with trifluoroacetic acid. The title compound was isolated andcharacterised as a bis dietylamine salt. Found: C, 62.21; H, 7.05; N,11.22. C₄₅ H₅₈ ClN₇ O₇ .1.5 H₂ O requires C, 62.02 H, 7.06; N, 11.25% ¹H NMR (d⁶ -DMSO) δ 10.1 (1H, s), 8.8 (1H, d), 8.5 (3H, s), 8.4 (1H, s),8.2 (1H, s), 7.9 (1H, s), 7.5-7.2 (7H, m), 4.8 (1H, m), 3.6-2.9 (4H, m),1.8 (3H, s), 1.6 (6H, q), 1.5 (6H, s).

EXAMPLE 136

(±)-5-(1-(3,5-dicarboxyphenylaminocarbonyl)-2-pentafluorophenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 except that(±)-1-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-pentafluorophenylethylaminewas used in step a instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethyl-amine.(±)-1-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-pentafluorophenylethylaminewas prepared by coupling BOC-pentafluorophenylalanine with3,5-dibenzyloxycarbonylaniline using PyBrOP, followed by treatment withtrifluoroacetic acid, ¹ H NMR (d⁶ -DMSO) δ 13.0 (2H, br s), 10.2 (1H,s), 8.9 (1H, d), 8.6 (2H, d), 8.5 (1H, t), 8.4 (1H, s), 8.2 (1H, d), 7.9(1H, s), 7.4 (1H, s), 4.8 (1H, m), 3.5 (1H, dd), 3.2 (1H, dd), 3.0 (2H,d), 1.9 (3H, s), 1.5 (6H, q), 1.4 (6H, s).

The compound was further characterised and tested as the di-10N-methyl-D-glucamine salt. Found: C, 50.83; H, 6.04; N, 8.17. C₅₁ H₆₆ F₅N₇ O₁₇ .3.3H₂ O requires C, 50.87; H, 6.08; N, 8.14%

EXAMPLE 137

5-(1S-(3-acetylaminosulphonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

a 1S-(3-acetylaminosulphonylphenylaminocarbonyl)-2-phenylethylamine

This was prepared as in example 99 step a except that acetic anhydridewas used to acylate the sulphonamide instead of trifluoroaceticanhydride.

b.5-(1S-(3-acetylaminosulphonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 128 except that the productof step a above was used as substrate instead of1S-(3-trifluoroacetylaminosulphonylphenylamino-carbonyl)-2-phenylethylaminein step b, ¹ H NMR (d⁶ -DMSO) δ 12.1 (1H, br s), 10.2 (1H, s), 8.9 (1H,d), 8.6 (3H, m), 8.0-7.2 (10H, m), 4.8 (1H, m), 3.6-2.9 (4H, m), 1.9(6H, m), 1.6 (6H, m), 1.5 (6H, m).

EXAMPLE 138

5-(1S-(3-acetylaminosulphonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole.Mixture of regioisomers at positions 5 and 6

This was prepared essentially as in example 99 except that1S-(3-acetylaminosulphonylphenylaminocarbonyl)-2-phenylethylamine wasused in step b instead of1S-(3-trifluoroacetylaminosulphonylphenylaminocarbonyl)-2-phenylethylamine,¹ H NMR (d⁶ -DMSO) δ 12.1 (1H, br s), 11.5 (1H, s), 10.3 (1H, 2×s), 8.8(1H, 2×d), 8.7-7.2 (13H, m), 6.6 and 6.5 (1H, m), 4.8 (1H, m), 3.6-2.8(4H, m), 1.9 (6H, m), 1.6 (6H, m), 1.5 (6H, m).

EXAMPLE 139

5-(1S-(3-benzoylaminosulphonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 137 except that benzoylchloride was used as acylating agent during the course of step a insteadof acetic anhydride, ¹ H NMR (d⁶ -DMSO) δ 12.8 (1H, br s), 10.1 (1H, s),8.8 (1H, d), 8.5 (3H, m), 8.3-7.2 (16H, m), 4.8 (1H, m), 3.6-2.9 (4H,m), 1.9 (3H, m), 1.6 (6H, m), 1.5 (6H, m).

EXAMPLE 140

5-(1S-(2-methoxy-5-carboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 except that1S-(2-methoxy-5-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminewas used in step a instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine. The1S-(2-methoxy-5-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylaminewas prepared by coupling BOC-L-phenyl-alanine and2-methoxy-5-benzyloxycarbonylaniline in the presence of PyBROP, followedby treatment with trifluoroacetic acid, ¹ H NMR (d⁶ -DMSO) δ 12.7 (2H,br s), 9.4 (1H, s), 8.8 (1H, d), 8.5 (1H, s), 8.4 (1H, s), 8.2 (1H, t),7.7 (2H, m), 7.3 (7H, m), 4.8 (1H, m), 3.9 (3H, s), 3.4-2.8 (4H, m), 1.9(3H, s), 1.6 (6H, q), 1.4 (6H, s).

The compound was further characterised and tested as theN-methyl-D-glucamine salt. Found: C, 59.15; H, 7.00; N, 9.41. C₄₄ H₅₆ N₆O₁₁ .2.75 H₂ O requires C, 59.08 H, 6.93; N, 9.40%

EXAMPLE 141

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(2-naphthalenenemethylaminocarbonyl)-indole.Mixture of regioisomers at positions 5 and 6

This compound was prepared essentially as in example 130 except thatindole-5,6-dicarboxylic acid anhydride was used in step a instead ofbenzimidazole-5,6-dicarboxylic acid anhydride ¹ H NMR (d⁶ -DMSO) δ 11.6(1H, br s), 10.2 (1H, s), 9.3 (1H, t), 8.8 (1H, d), 8.7 (2H, s), 8.4(2H, s), 8.1 (1H, s), 7.8 (4H, m), 7.6-7.2 (l1H, m), 6.5 (1H, s), 4.8(3H, m), 3.5 (1H, dd), 3.0 (1H, dd).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt

EXAMPLE 142

(±)-5-(1-(3,5-dicarboxyphenylaminocarbonyl)-2-(2,6-difluorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 except that(±)-1(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-(2,6-difluorophenyl)ethylaminewas used in step a instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine.(±)-1-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-(2,6-difluorophenyl)ethylaminewas prepared by coupling BOC-2,6-difluorophenylalanine with3,5-dibenzyloxycarbonylaniline using PyBrOP, followed by treatment withtrifluoroacetic acid, ¹ H NMR (d⁶ -DMSO) δ 13.3 (2H, br s), 12.9 (1H, brs), 10.2 (1H, s), 8.9 (1H, d), 8.7 (2H, d), 8.6 (1H, t), 8.4 (1H, s),8.2 (1H, d), 7.9 (1H, m), 7.4 (1H, m), 7.3 (1H, m), 7.1 (2H, m), 4.8(1H, m), 3.5 (1H, dd), 3.1 (1H, dd), 2.9 (2H, d), 1.9 (3H, s), 1.6 (6H,m), 1.5 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt

EXAMPLE 143

5-(1R-(3,5-dicarboxyphenylaminocarbonyl)-2-(2-fluorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 except that1R-(3,5-di-benzyloxycarbonylphenylaminocarbonyl)-2-(2-fluorophenyl)ethylaminewas used in step a instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine. The1R-(3,5-di-benzyloxycarbonylphenylaminocarbonyl)-2-(2-fluorophenyl)ethylaminewas prepared by coupling BOC-D-2-fluorophenylalanine and3,5-dibenzyloxycarbonylaniline in the presence of PyBROP, followed bytreatment with trifluoroacetic acid, ¹ H NMR (d⁶ -DMSO) δ 13.0 (3H, brs), 10.2 (1H, s), 8.9 (1H, d), 8.7 (2H, s), 8.6 (1H, t), 8.4 (1H, s),8.2 (1H, s), 7.9 (1H, d), 7.4-7.2 (4H, m), 7.1 (1H, s), 4.8 (1H, m),3.6-2.9 (4H, m), 1.8 (3H, s), 1.6 (6H, m), 1.3 (6H, m).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt

EXAMPLE 144

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(2,4-difluorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 except that1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-(2,4-difluorophenyl)ethylaminewas used in step a instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine.1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-(2,4-difluorophenyl)ethylaminewas prepared by coupling BOC-L-2,4-difluorophenylalanine with3,5-dibenzyloxycarbonylaniline using PyBrOP, followed by treatment withtrifluoroacetic acid, ¹ H NMR (d⁶ -DMSO) δ 13.2 (3H, br s), 10.2 (1H,s), 8.9 (1H, d), 8.7 (2H, d), 8.6 (1H, t), 8.4 (1H, s), 8.2 (1H, t), 7.5(1H, m), 7.3 (2H, m), 7.2 (1H, s), 7.1 (1H, m), 4.8 (1H, m)), 3.5 (1H,dd), 3.0 (3H, m), 1.9 (3H, s), 1.6 (6H, q) , 1.5 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt

EXAMPLE 145

5-(1R-(3,5-dicarboxyphenylaminocarbonyl)-2-(2,4-difluorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 except that1R-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-(2,4-difluorophenyl)ethylaminewas used in step a instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine.1R-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-(2,4-difluorophenyl)ethylaminewas prepared by coupling BOC-D-2,4-difluorophenylalanine with3,5-dibenzyloxycarbonylaniline using PyBrOP, followed by treatment withtrifluoroacetic acid, ¹ H NMR (d⁶ -DMSO) δ 13.2 (3H, br s), 10.2 (1H,s), 8.9 (1H, d), 8.7 (2H, d), 8.6 (1H, t), 8.4 (1H, s), 8.2 (1H, t), 7.5(1H, m), 7.3 (2H, m), 7.2 (1H, s), 7.1 (1H, m), 4.8 (1H, m), 3.5 (1H,dd), 3.0 (3H, m), 1.9 (3H, s), 1.6 (6H, q) , 1.5 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt

EXAMPLE 146

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(2,6-difluorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 except that1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-(2,6-fluorophenyl)ethylaminewas used in step a instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine.1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-(2,6-difluorophenyl)ethylaminewas prepared by coupling BOC-L-2,6-difluorophenylalanine with3,5-dibenzyloxycarbonylaniline using PyBrOP, followed by treatment withtrifluoroacetic acid, ¹ H NMR (d⁶ -DMSO) δ 13.3 (2H, br s), 12.9 (1H, brs), 10.2 (1H, s), 8.9 (1H, d), 8.7 (2H, d), 8.6 (1H, t), 8.4 (1H, s),8.2 (1H, d), 7.9 (1H, m), 7.4 (l_(H), m), 7.3 (1H, m), 7.1 (2H, m), 4.8(1H, m), 3.5 (1H, dd), 3.1 (1H, dd), 2.9 (2H, d), 1.9 (3H, s), 1.6 (6H,m), 1.5 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt

EXAMPLE 147

5-(1R-(3,5-dicarboxyphenylaminocarbonyl)-2-(2,6-difluorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 except that1R-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-(2,6-difluorophenyl)ethylaminewas used in step a instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine.1R-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-(2,6-difluorophenyl)ethylaminewas prepared by coupling BOC-D-2,6-difluorophenylalanine with3,5-dibenzyloxycarbonylaniline using PyBrOP, followed by treatment withtrifluoroacetic acid, ¹ H NMR (d⁶ -DMSO) 3 13.3 (2H, br s), 12.9 (1H, brs), 10.2 (1H, s), 8.9 (1H, d), 8.7 (2H, d), 8.6 (1H, t), 8.4 (1H, s),8.2 (1H, d), 7.9 (1H, m), 7.4 (1H, m), 7.3 (1H, m), 7.1 (2H, m), 4.8(1H, m), 3.5 (1H, dd), 3.1 (1H, dd), 2.9 (2H, d), 1.9 (3H, s), 1.6 (6H,m), 1.5 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt

EXAMPLE 148

5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-pentafluorophenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 except that1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-pentafluorophenylethylaminewas used in step a instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine.1S-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-pentafluorophenylethylaminewas prepared by coupling BOC-L-pentafluorophenylalanine with 3,5-dibenzyloxycarbonylaniline using PyBrOP, followed by treatment withtrifluoroacetic acid, ¹ H NMR (d⁶ -DMSO) δ 13.0 (2H, br s), 10.2 (1H,s), 8.9 (1H, d), 8.6 (2H, d), 8.5 (1H, t), 8.4 (1H, s), 8.2 (1H, d), 7.9(1H, S), 7.4 (1H, s), 4.8 (1H, m), 3.5 (1H, dd), 3.2 (1H, dd), 3.0 (2H,d), 1.9 (3H, s), 1.5 (6H, q), 1.4 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt

EXAMPLE 149

5-(1R-(3,5-dicarboxyphenylaminocarbonyl)-2-pentafluorophenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 except that1R-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-pentafluorophenylethylaminewas used in step a instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine.1R-(3,5-dibenzyloxycarbonylphenylaminocarbonyl)-2-pentafluorophenylethylaminewas prepared by coupling BOC-pentafluorophenylalanine with3,5-dibenzyloxycarbonylaniline using PyBrOP, followed by treatment withtrifluoroacetic acid, ¹ H NMR (d⁶ -DMSO) δ 13.0 (2H, br s), 10.2 (1H,s), 8.9 (1H, d), 8.6 (2H, d), 8.5 (1H, t), 8.4 (1H, s), 8.2 (1H, d), 7.9(1H, s), 7.4 (1H, s), 4.8 (1H, m), 3.5 (1H, dd), 3.2 (1H, dd), 3.0 (2H,d), 1.9 (3H, s), 1.5 (6H, q), 1.4 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt

EXAMPLE 150

5-(1R-(3,5-dicarboxyphenylaminocarbonyl)-2-(3-fluorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole

This was prepared essentially as in example 79 except that1R-(3,5-di-benzyloxycarbonylphenylaminocarbonyl)-2-(3-fluorophenyl)ethylaminewas used in step a instead of1S-(3-benzyloxycarbonylphenylaminocarbonyl)-2-phenylethylamine. The1R-(3,5-di-benzyloxycarbonylphenylaminocarbonyl)-2-(3-fluorophenyl)ethylaminewas prepared by coupling BOC-D-3-fluorophenylalanine and3,5-dibenzyloxycarbonylaniline in the presence of PyBROP, followed bytreatment with trifluoroacetic acid, ¹ H NMR (d⁶ -DMSO) δ 13.0 (3H, brs), 10.2 (1H, s), 8.9 (1H, d), 8.7 (2H, s), 8.5 (1H, t), 8.4 (1H, s),8.2 (1H, s), 7.9 (1H, s), 7.4 (1H, m), 7.2 (4H, m), 4.8 (1H, m), 3.6-2.9(4H, m), 1.8 (31H s), 1.7 (6H, q), 1.5 (6H, s).

The compound was further characterised and tested as thedi-N-methyl-D-glucamine salt

The compounds of the examples were tested for binding at the CCK_(B)receptor in mouse cortical membranes by means of a radioligand bindingassay. The procedure was as follows:

The whole brains from male mice (CD1 22-25 g; Charles River) wereremoved and placed in ice-cold buffer (pH7.2 @ 21±3°) of the followingcomposition (mM); 10 HEPES, 130 NaCl, 4.7 KCl, 5 MgCl₂, 1 EDTA andcontaining 0.25g.⁻¹ bacitracin. The cortex was dissected, weighed andhomogenised in 40ml ice-cold buffer using a Teflon-in-glass homogeniser.The homogenate was centrifuged at 39,800g for 20 min at 4°, thesupernatant discarded and the pellet resuspended by homogenisation infresh buffer. The homogenate was recentrifuged (39,800 g; 20 min @ 4°)and the final pellet was resuspended in HEPES buffer to give a tissueconcentration of 2 mg.ml⁻¹ (original wet weight).

The membranes (400 ml) were incubated for 150 min at 21±3° in a finalvolume of 0.5 ml with HEPES buffer containing ¹²⁵ I!-CCK8S (0.05 ml; 200pM NEN 2200 Ci.mmol⁻¹) and competing compound. Total and non-specificbinding of ¹²⁵ I!-CCK8S were defined using 0.05 ml of buffer and 0.05 mlof 10 mM L-365,260, respectively. The assay was terminated by rapidfiltration through pre-soaked Whatman GF/B filters using a Brandell Cellharvester. The filters were washed (3×3 ml) with ice-cold 50 mM Tris-HCl(pH7.4 @ 4° C.) and bound radioactivity determined by counting (1 min.)in a gamma-counter.

The results obtained from the CCKB assays are set out in Table 1.

                  TABLE 1                                                         ______________________________________                                        Example  CCK.sub.B pK.sub.i                                                                         Example  CCK.sub.B pK.sub.i                             ______________________________________                                        1        5.5          38       7.5                                            2        5.5          39       6.4                                            3        6.4          40       6.8                                            4        5.5          41       7.8                                            5        6.0          42       7.8                                            6        6.0          43       5.8                                            7        5.8          44       8.7                                            8        5.3          45       7.1                                            9        6.6          46       6.7                                            10       5.8          47       6.8                                            11       5.9          48       6.2                                            12       5.9          49       5.6                                            13       5.7          50       6.6                                            14       6.0          51       8.0                                            15       7.9          52       7.2                                            16       5.6          53       8.1                                            19       5.7          54       8.1                                            20       5.0          55       8.2                                            22       5.9          56       7.0                                            24       8.9          57       7.7                                            26       7.9          58       6.5                                            27       8.5          59       6.9                                            28       8.5          60       7.8                                            29       8.1          61       8.4                                            30       7.6          62       7.8                                            31       7.9          63       8.4                                            32       8.4          64       7.2                                            33       5.6          65       7.3                                            34       8.1          66       5.8                                            35       7.2          67       6.3                                            36       9.4          68       5.9                                            37       8.4          69       6.5                                            70       8.1          102      7.4                                            71       6.4          103      7.0                                            72       6.0          104      8.9                                            73       6.3          105      8.3                                            74       7.6          106      5.7                                            75       7.8          108      5.9                                            76       6.2          109      6.7                                            77       6.6          110      6.4                                            78       7.3          111      5.8                                            79       7.7          112      8.1                                            80       8.4          113      6.9                                            81       6.1          114      6.0                                            82       7.0          115      7.6                                            83       7.8          116      8.5                                            84       8.6          117      6.1                                            85       8.3          118      6.7                                            86       7.5          119      6.2                                            87       9.1          120      6.2                                            88       8.3          122      8.3                                            89       6.2          123      7.9                                            90       8.2          124      6.5                                            91       7.4          125      8.9                                            92       6.5          126      6.3                                            93       8.1          127      7.6                                            94       6.7          128      8.2                                            95       5.9          129      6.7                                            96       6.3          130      7.6                                            97       9.1          131      8.4                                            98       8.4          132      8.4                                            99       8.4          134      7.6                                            100      7.9          135      8.3                                            101      7.4          136      8.9                                            137      7.7          139      7.8                                            138      8.1                                                                  ______________________________________                                    

The compounds of the examples were also tested for gastrin antagonistactivity in an immature rat stomach assay. The procedure was as follows:

The oesophagus of immature rats (33-50 g, ca. 21 days old) was ligatedat the level of the cardiac sphincter and the duodenal sphincter wascannulated. The stomach was excised and flushed with ca. 1 ml ofunbuffered physiological saline solution. The fundus was punctured andcannulated. A further 4-5 ml of unbuffered solution was flushed throughthe stomach to ensure the preparation was not leaking. The stomach waslowered into a jacketed organ bath containing 40 ml of buffered solutioncontaining 3×10⁻⁸ M 5-methylfurmethide, maintained at 37° and gassedvigorously with 95% O₂ /5% CO₂. The stomach was continuously perfused ata rate of 1 ml min⁻¹ with unbuffered solution gassed with 100% O₂ withthe perfusate passing over an internally referenced pH-electrode fixed12 cm above the stomach.

After 120 min of stabilisation the drugs were added directly to theserosal solution in the organ bath and after a further 60 min cumulativepentagastrin dose-response curves were started. Changes in acidsecretion were monitored and the curves analysed according to Blacket.al., Br. J. Pharmacol., 1985, 86, 581.

The results obtained from the gastrin assays are set out in Table 2.

                  TABLE 2                                                         ______________________________________                                        Example  Gastrin pK.sub.B                                                                            Example  Gastrin pK.sub.B                              ______________________________________                                        1        5.8           41       7.8                                           2        6.0           42       9.3                                           3        6.7           44       8.7                                           4        6.3           46       7.1                                           5        6.8           47       8.3                                           7        6.4           48       7.0                                           8        5.9           50       6.9                                           9        6.3           51       7.6                                           10       6.5           53       7.9                                           11       6.6           54       8.1                                           12       5.9           55       8.3                                           13       6.4           56       7.1                                           14       6.5           57       7.7                                           15       8.2           58       7.5                                           16       6.2           59       7.5                                           21       5.3           60       8.1                                           23       7.4           61       8.7                                           24       9.5           62       8.2                                           26       9.3           63       9.1                                           27       9.2           65       8.2                                           28       9.7           67       6.8                                           29       9.2           69       7.1                                           30       9.1           70       7.8                                           31       8.9           71       7.0                                           32       9.1           72       6.3                                           33       7.7           73       7.2                                           34       8.7           74       9.0                                           35       8.7           75       7.7                                           37       8.4           76       6.9                                           38       7.1           77       7.0                                           39       6.8           78       8.6                                           40       7.3           79       7.0                                           80       8.2           112      8.2                                           81       6.9           113      7.2                                           82       6.9           115      8.2                                           83       7.2           116      9.0                                           85       8.9           118      6.7                                           86       7.7           122      9.1                                           87       9.6           123      8.5                                           88       8.6           124      6.8                                           89       6.8           125      9.4                                           90       8.0           126      7.0                                           91       8.0           127      7.5                                           92       6.8           128      8.6                                           93       7.7           131      9.7                                           95       5.9           132      9.0                                           100      7.5           133      8.1                                           103      7.8           134      8.8                                           104      8.6           135      8.9                                           105      8.5           136      9.5                                           108      6.1           137      7.8                                           109      6.9           139      7.1                                           110      6.9                                                                  ______________________________________                                    

The compounds of the examples were also tested in a CCK_(A) as follows:

The pancreatata were removed from male guinea-pigs (200-300 g; DunkinHartley) and placed in ice-cold HEPES buffer (pH 7.2 @ 21 ±3). Thepancreatata were homogenised in 40 ml ice-cold HEPES buffer using apolytron (Brinkmann, PT10, setting 10) 4×1 second. The homogenate wascentrifuged at 39,800 g for 15 min at 4°. The supernatant was discardedand the pellet re-suspended using a Teflon-in-glass homogeniser in 20volumes of fresh buffer and re-centrifuged as above.

The final pellet was re-suspended using a Teflon-in-glass homogeniser toa tissue concentration of 1 mg.ml⁻¹ (original wet weight), and filteredthrough 500 μm pore-size Nytex mesh.

The membranes (400 μl; containing 0.375 μM PD134,308) are incubated for150 minutes at 21±3° in a final volume of 0.5 ml with HEPES buffercontaining ¹²⁵ I!-CCK₈ (S) (50 μl; 200 μM) and competing compound. Totaland non-specific binding of ¹²⁵ I!-CCK₈ (S) are defined using 50 μl ofbuffer and 50 μl of 100 nM L-364,718 respectively. The assay isterminated by rapid filtration through pre-soaked Whatman GF/B filtersusing a Brandell Cell Harvester. The filters were washed (3×3 ml) withice-cold 50 mM Tris HCl (pH 7.4 at 4°) and bound radioactivity isdetermined by counting (1 min) in a gamma counter.

The results are set out in Table 3.

                  TABLE 3                                                         ______________________________________                                        Example  CCK.sub.A pK.sub.i                                                                         Example  CCK.sub.A pK.sub.i                             ______________________________________                                        1        5.1          45       6.1                                            2        4.9          46       5.1                                            3        5.5          47       5.2                                            4        5.4          48       5.5                                            5        5.2          49       5.6                                            6        5.6          50       6.1                                            7        5.8          52       5.9                                            8        6.0          53       6.1                                            15       6.1          54       5.9                                            16       5.5          55       5.8                                            17       4.8          57       5.7                                            18       6.3          58       5.0                                            19       5.3          59       5.1                                            20       5.0          60       5.6                                            21       5.2          61       5.2                                            22       5.4          62       5.4                                            24       5.7          66       5.0                                            26       5.5          67       5.7                                            27       5.6          68       5.9                                            28       5.4          69       5.1                                            29       5.4          70       5.1                                            30       5.2          71       5.3                                            31       5.5          72       5.6                                            33       5.2          73       5.2                                            34       6.1          74       5.3                                            36       5.5          75       6.1                                            37       5.6          76       <5.0                                           39       4.9          77       <5.0                                           40       6.3          78       5.3                                            41       5.7          79       6.0                                            42       5.5          80       6.1                                            44       5.6          81       5.5                                            82       5.7          111      <5.0                                           83       6.4          112      <5.0                                           84       6.2          113      5.2                                            85       5.5          114      5.5                                            86       5.0          115      5.6                                            87       5.5          116      5.6                                            88       5.6          117      5.8                                            89       5.1          118      6.3                                            90       5.3          119      5.6                                            91       5.3          120      6.0                                            92       4.9          121      5.1                                            93       5.6          122      5.4                                            94       5.0          123      6.3                                            95       5.8          124      5.7                                            96       5.7          125      5.7                                            97       6.3          126      5.3                                            98       6.7          127      5.9                                            99       5.4          128      5.7                                            100      6.4          129      5.1                                            101      6.6          130      5.4                                            102      5.9          131      5.3                                            103      5.2          132      5.4                                            104      6.5          133      5.1                                            105      6.8          134      6.1                                            108      <5.0         135      5.1                                            109      <5.0         136      <5.0                                           110      <5.0                                                                 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We claim:
 1. A compound of the formula ##STR22## wherein A representsindole or benzimidazole , wherein W and X replace hydrogen on adjacentcarbon atoms,m is from 0 to 6, provided that m is not more than 2 unlessR¹ is exclusively halo, each R¹ is independently selected from the groupconsisting of halo, amino, amidino, nitro, cyano, hydroxy, sulphamoyl,hydroxysulphonyl, carboxy, esterified carboxy, amidated carboxy,tetrazolyl, C₁ to C₈ alkyl, aryl, substituted aryl, C₁ to C₆hydroxyalkyl, C₁ to C₆ haloalkyl, C₁ to C₆ alkoxy, C₁ to C₆alkylcarboxyamino, HON═C--, R²⁷ --SO₂ --NH--, R²⁷ --SO₂ --NH--CO--, R²⁷--CO--, R²⁷ --CO--NH--, R²⁷ --CO--NH--SO₂ --, R²⁷ --CO--NH--SO-- and R²⁸--NH--SO₂ --,wherein R²⁷ is H, C₁ to C₆ alkyl, C₁ to C₆ haloalkyl, arylor substituted aryl, and R²⁸ is H, C₁ to C₆ alkyl, C₁ to C₆ haloalkyl,aryl, substituted aryl, --OH or --CN except that R²⁷ cannot be H whenattached to a sulphur atom, W is a carbonyl, sulphonyl or sulphinylgroup, and X is a carbonyl, sulphonyl or sulphinyl group, provided thatat least one of W and X contains carbonyl, Y is R³ --N(R⁴)-- or R^(3')--O--, wherein R³ is H or C₁ to C₁₅ hydrocarbyl, optionally substitutedby halogen, wherein up to two CH groups of the hydrocarbyl moietyoptionally may be replaced by a nitrogen atom, and wherein up to two CH₂groups of the hydrocarbyl moiety optionally may be replaced by an oxygenor sulphur atom, R^(3') is C₆ to C₁₅ hydrocarbyl, optionally substitutedby halogen, wherein up to two carbon atoms of the hydrocarbyl moietyoptionally may be replaced by a nitrogen oxygen or sulphur atom, and R⁴is H, C₁ to C₃ alkyl, carboxymethyl or esterified carboxymethyl,provided that Y does not contain a --O--O-- group, and Z is selectedfromi) --O--R⁵ wherein R⁵ is H, C₁ to C₅ alkyl, phenyl, substitutedphenyl, benzyl or substituted benzyl; ii) --N(Q)--Hwherein Q is H, C₁ toC₅ hydrocarbyl, or R⁶ --U, wherein R⁶ is a bond or C₁ to C₅ alkylene andU is aryl, substituted aryl, heterocyclic, substituted heterocyclic orcycloalkyl, (iii) ##STR23## wherein a is 0 or 1 and b is from 0 to 3, R⁷is H or methyl,R⁸ is H or methyl; or R⁸ is CH₂ ═ and Q' is absent; or R⁷and R⁸ are linked to form a 3- to 7-membered ring, R⁹ is a bond or C₁ toC₅ hydrocarbylene, G is a bond, --CHOH-- or --C(0)-- Q' is as recitedabove for Q or Q' is R⁶ --(C(0))_(d) --L--(C(0))_(e) --R⁵, wherein R⁵and R⁶ are as defined above, L is 0, S or --N(R¹⁰)--, wherein R¹⁰ is asdefined above for R⁴, and d and e are 0 or 1, provided that d+e<2); orQ' and R⁸, together with the carbon atom to which they are attached,form a 3- to 7-membered ring, Q is as defined above; or Q and R⁸together form a group of the formula --(CH₂)_(f) --V--(CH₂)_(g) whereinV is --S--, --S(0)--, S(0)₂ --, --CH₂ --, --CHOH-- or --C(0)--, f isfrom 0 to 2 and g is from 0 to 3; or, when Q' is --R⁶ --U and U is anaromatic group, Q may additionally represent a methylene link to U,which link is ortho to the R⁶ link to U, T is H, cyano, C₁ to C₄ alkyl,--CH₂ OH, carboxy, esterified carboxy, amidated carboxy or tetrazolyl;and iv) ##STR24## wherein R⁵ and R¹ are as defined above, R¹¹ is asdefined above for R⁴, and R¹² and R¹³ are independently a bond or C₁ toC₃ alkylene, provided that R¹² and R¹³ together provide from 2 to 4carbon atoms in the ring,wherein said heterocyclic groups are selectedfrom the group consisting of benzimidazolyl, thienyl, furanyl, pyrrolyl,imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, pyrrolidinyl,pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl,tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl,piperidyl, piperazinyl, morpholinyl, thionaphthyl, benzafuranyl,isobenzofuryl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl,7-azaindolyl, isoindazolyl, benzopyranyl, coumarinyl, isocoumarinyl,quinolyl, isoquinolyl, naphthridinyl, cinnolinyl, quinazolinyl,pyridopyridyl, benzoxazinyl, quinoxadinyl, chromenyl, chromanyl,isochromanyl and carbolinyl, and wherein said substituted aryl, benzyl,phenyl, or heterocyclic groups independently are substituted with up to3 substituents, independently selected from the group consisting ofhalo, amino, amidino, nitro, cyano, hydroxy, sulphamoyl,hydroxysulphonyl, carboxy, esterified carboxy, amidated carboxy,tetrazolyl, C₁ to C₈ alkyl, C₁ to C₆ hydroxyalkyl, C₁ to C₆ haloalkyl,C₁ to C₆ alkoxy, C₁ to C₆ alkylcarboxyamino, HON═C--, R²⁷ --SO₂ --NH--,R²⁷ --SO₂ --NH--CO--, R²⁷ --CO--, R²⁷ --CO--NH--, R²⁷ --CO--NH--SO₂ --,R²⁷ --CO--NH--SO-- and R²⁸ --NH--SO₂ --, or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1, of theformula ##STR25## wherein R³² is H, C₁ to C₃ alkyl or C₁ to C₃alkylcarboxy; and L' is --NR³² --.
 3. A compound according to claim 1wherein R³ is C₆ to C₈ straight or branched chain alkyl, or R³--(CH₂)_(p) -- wherein R²³ is selected from phenyl, 1-naphthyl,2-naphthyl, indolyl, norbornyl, adamantyl, cyclohexyl or cycloheptyl,and p is from 0 to
 3. 4. A compound according to claim 1 wherein W iscarbonyl and X is sulphonyl.
 5. A compound according to claim 1 whereinW is carbonyl and X is carbonyl.
 6. A compound according to claim 1wherein W is sulphonyl and X is carbonyl.
 7. A compound according toclaim 1 wherein m is
 0. 8. A compound according to claim 1 wherein--X--Y is --CONR³ R⁴, and --W--Z is r ##STR26## wherein R²⁹, R³⁰ and R³¹are independently H or C₁ to C₃ alkyl;U' is an optionally substitutedaromatic group; n is 1 or 2; T¹ is --CO₂ H, tetrazolyl, esterifiedcarboxy, amidated carboxy, R²⁷ --SO₂ --NH--, R²⁷ --SO₂ --NH--CO--, R²⁷--CO--, R²⁷ --CO--NH--, R²⁷ --CO--NH-- SO₂ --, R²⁷ --CO--NH--SO-- or R²B--NH--SO₂ --, each T¹ being independently selected from the foregoingwhen n is 2; and c is from 0 to
 2. 9. A compound selectedfrom5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole,5-(1R-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole,5-(1R-(3,5-dicarboxyphenylaminocarbonyl)-2-(2-fluorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole,5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(2-fluorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-indole,5-(1R-(3,5-dicarboxyphenylaminocarbonyl)-2-(4-hydroxyphenyl)ethylaminocarbonyl)-6-(1-adamantanemethyl-aminocarbonyl)-indole,5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(4-hydroxyphenyl)ethylaminocarbonyl)-6-(1-adamantanemethyl-aminocarbonyl)-indole,5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole,5-(1R-(3,5-dicarboxyphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole,5-(1R-(3,5-dicarboxyphenylaminocarbonyl)-2-(2-fluorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole,5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(2-fluorophenyl)-ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole,5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(3-fluorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethyl-aminocarbonyl)-benzimidazole,5-(1R-(3,5-dicarboxyphenyl-aminocarbonyl)-2-(3-fluorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethyl-aminocarbonyl)-benzimidazole,5-(1R-(3,5-dicarboxyphenylaminocarbonyl)-2-(4-hydroxyphenyl)ethyl-aminocarbonyl)-6-(1-adamantanemethyl-aminocarbonyl)-benzimidazole,5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(4-hydroxyphenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole,5-(1S-(3,5-dicarboxyphenylaminocarbonyl)-2-(2-fluorophenyl)ethylaminocarbonyl)-6-(cycloheptanemethylaminocarbonyl)-benzimidazole,5-(1S-(3-benzoylaminosulphonylphenylaminocarbonyl)-2-phenylethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole,and5-(1S-(3-benzoylaminosulphonylphenylaminocarbonyl)-2-(2-fluorophenyl)ethylaminocarbonyl)-6-(1-adamantanemethylaminocarbonyl)-benzimidazole.10. A pharmaceutical composition comprising a compound according toclaim 1, together with a pharmaceutically acceptable diluent or carrier.11. A method of making a compound according to claim 1 wherein W iscarbonyl, said method including the step of reacting a compound of theformula YH, wherein Y is as defined in claim 1, with a compound of theformula (II) ##STR27## wherein B represents ##STR28## and A, R¹, m, andX are as defined in claim
 1. 12. A method of making a compound accordingto claim 1 wherein W is sulphonyl, said method comprising the step ofreacting a compound of the formula R³ -Hal with a compound of theformula ##STR29## wherein Hal represents a halogen atom, B is ##STR30##and R³ is as defined in claim 1, and then reacting the product with analkoxide.
 13. A method of making a compound according to claim 1 whereinW or X is sulphoxide, said method comprising the step of reacting acompound of the formula R³ -Hal with a compound of the formula:##STR31## wherein Hal represents a halogen atom, B is ##STR32## and R³is as defined in claim 1, and then reacting the product with analkoxide.